CN105073730B - monocyclic pyridine derivatives - Google Patents

Abstract

The present invention discloses a compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof:wherein n represents 0 to 2; a represents an arylene or heteroarylene group; g represents a single bond, an oxygen atom or-CH₂-; e represents a nitrogen-containing non-aromatic heterocycle; r¹Represents alkoxy, alkoxyalkoxy or the like; r²Represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a hydroxyalkyl group, a nitrogen-containing non-aromatic heterocyclic group or the like; r³Represents a hydrogen atom, an alkyl group, an alkoxy group or the like; and R is⁴Represents C_1‑6Alkyl with the proviso that when E represents an azetidine ring and R²Or R³When present on a nitrogen atom of the azetidine ring, the R²Or R³And does not represent a hydrogen atom.

Description

monocyclic pyridine derivatives

technical field

The present invention relates to a monocyclic pyridine derivative with FGFR inhibitory effect or a pharmaceutically acceptable salt thereof, and its medical application.

All references cited herein are hereby incorporated by reference in their entirety.

Background technique

FGF (Fibroblast Growth Factor) is known as a growth factor for controlling various physiological functions such as cell growth, cell migration, cell infiltration, cell survival, differentiation induction, wound healing, and angiogenesis.

FGF controls different physiological functions through FGF receptors (FGFRs: FGFR1, FGFR2, FGFR3 and FGFR4), ie, receptor tyrosine kinases. Each FGFR contains three types of domains: an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. When a FGF binds to the extracellular domain of a FGFR, a dimer of the receptor is formed. Thereafter, the intracellular tyrosine kinase is activated and then mainly through a MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) channel or a PI3K (phosphatidylinositol 3-kinase)/Akt Channels transmit intracellular signals.

Meanwhile, different cancers such as breast cancer, bladder cancer, EMS (8p11 myeloproliferative syndrome), gastric cancer, endometrial cancer, and prostate cancer have been reported to be caused by abnormal FGF/FGFR signaling accompanied by enhanced FGF production, FGFR gene amplification, As a result of induction of FGFR overexpression, FGFR fusion protein production, FGFR mutation, and the like (Non-Patent Document 1). In addition, the following have been reported as cancers with abnormal FGF/FGFR signaling: non-small cell lung cancer, small cell lung cancer, ovarian cancer, sarcoma, colon cancer, melanoma, glioblastoma, astrocytes cell tumor, and head and neck cancer (Non-Patent Document 2 and 3), thyroid cancer (Non-Patent Document 4), pancreatic cancer (Non-Patent Document 5 and 6), liver cancer (Non-Patent Document 7), skin cancer (Non-Patent Document 8 ), kidney cancer (Non-Patent Document 9), and lung squamous cell carcinoma (Non-Patent Documents 10, 11, and 12).

Additionally, this FGF/FGFR signaling is one of the major angiogenic signals in endothelial cells, along with VEGF (vascular endothelial growth factor)/KDR (kinase insertion domain receptor-containing) signaling, and has been reported to be involved in tumor stromal (fibroblast cells) and cancer cells (Non-Patent Document 1).

Therefore, an FGFR inhibitor targeting FGF/FGFR signaling is expected to act as an antineoplastic agent against cancers accompanied by abnormal FGF/FGFR signaling based on its inhibitory effect against signaling abnormalities and its inhibitory effect against angiogenic signaling . Recently, a selective FGFR inhibitor thought to be less susceptible to the antagonistic effect of another signal, such as selective FGFR1, FGFR2 or FGFR3, has been reported, which are structurally distinct in the compounds of the present invention. However, in development as an antitumor drug for humans, this selective FGFR inhibitor lags behind an antitumor drug that simultaneously targets both FGF/FGFR signaling and VEGF/KDR signaling, and is not yet on the market. Upward promotion (Non-Patent Documents 13 and 14; Patent Documents 1 and 2). Patent Document 3 discloses pyrimidine derivatives but does not disclose the inhibitory action against signaling abnormalities of FGF/FGFR signaling. Patent Document 4 discloses pyridine derivatives or pyrimidine derivatives that inhibit angiogenesis induced by VEGF and FGF. However, none of these documents disclose the compounds of the present invention.

reference list

patent documents

[Patent Document 1] International Publication No. WO 2008/075068

[Patent Document 2] International Publication No. WO 2006/000420

[Patent Document 3] International Publication No. WO 2002/032872

[Patent Document 4] International Publication No. WO 2004/020434

non-patent literature

[Non-Patent Document 1] Nicholas et al., "Fibroblast growth factor signaling: from development to cancer (fibroblast growth factor signaling: from development to cancer)", Nature Reviews Cancer ("Natural Cancer Review"), 2010; 10: 116-129

[Non-Patent Document 2] Jorgen WESCHE et al., Fibroblast growth factors and their receptors in cancer (fibroblast growth factors and their receptors in cancer), Biochem J. ("Biochemical Journal"), 2011: 437; 199- 213

[Non-Patent Document 3] Gennaro Daniele et al., FGF Receptor Inhibitors: Role in Cancer Therapy (FGF Receptor Inhibitor: Role in Cancer Therapy), Curr Oncol Rep. ("Latest Oncology Report"), 2012; 14: 111-119

[Non-Patent Document 4] Rosanne St.Bernard et al., Fibroblast Growth Factor Receptors as Molecular Targets in Thyroid Carcinoma (Fibroblast Growth Factor Receptors as Molecular Targets in Thyroid Tumors), Endocrinology ("Endocrinology"), 2005; 146:1145-1153

[Non-Patent Document 5] Toshiyuki Ishiwata et al., Enhanced Expression of Fibroblast Growth Factor Receptor 2IIIc Promotes Human Pancreatic Cancer Cell Proliferation (enhanced expression of fibroblast growth factor receptor 2IIIc promotes proliferation of human pancreatic cancer cells), AmJ Pathol. ("American Disease Journal of Science), 2012;180:1928-1941

[Non-Patent Document 6] G Chen et al., Inhibition of endogenous SPARC enhancespancreatic cancer cell growth: modulation by FGFR1-III isoform expression (inhibition of endogenous SPARC enhances pancreatic cancer cell growth: regulated by FGFR1-III isoform expression), Br J Cancer ("British Journal of Cancer"), 2010;102:188-195

[Non-Patent Document 7] Dorothy M. French et al., Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models (Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models), PLoS One. , 2012;7:e36713

[Non-Patent Document 8] Armelle Logie et al., Activating mutations of the tyrosinekinase receptor FGFR3 are associated with benign skin tumors in mice and humans (activating mutations of the tyrosine kinase receptor FGFR3 in mice and humans are associated with benign skin tumors), Hum MolGenet ("Human Molecular Genetics"), 2005;14:1153-1160

[Non-Patent Document 9] Tsimafeyeu I et al., Overexpression of fibroblast growthfactor receptors FGFR1and FGFR2in renal cell carcinoma (overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma), Scand J Urol Nephrol ("Scand J Urol Nephrol") Navian Journal of Urology and Nephrology), 2011;45:190-195

[Non-Patent Document 10] Jonathan Weiss et al., Frequent and FocalFGFR1Amplification Associates with Therapeutically Tractable FGFR1Dependency in Squamous Cell Lung Cancer (FGFR1 amplification in squamous cell lung cancer and focus is related to therapeutically tame FGFR1 dependence), Sci Transl Med. ("Science Translational Medicine"), 2010; 2:62 Issue 62-93

[Non-Patent Document 11] Hidefumi Sasaki et al., Increased FGFR1 copy number in lungsquamous cell carcinomas (increased FGFR1 copy number in lung squamous cell carcinoma), Mol Med Report. ("Molecular Medicine Report"), 2012; 5: 725 -728

[Non-Patent Document 12] The Cancer Genome Atlas Research Network, Comprehensive genomic characterization of squamous cell lung cancers (Research Network of Cancer Genome Atlas, Genome-wide Characterization of Squamous Cell Lung Cancer), Nature ("Nature"), 2012; 489: 519 -525

[Non-Patent Document 13] Paul R Gavine et al., AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family Bioavailable, potent and selective inhibitors), Cancer Res. ("Cancer Research"), 2012;72:2045-2056

[Non-Patent Document 14] Vito Guagnano et al., Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase (Fibroblast Growth Factor of Receptor Tyrosine Kinase A potent and selective inhibitor of the receptor family 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl The discovery of -piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), J Med Chem. ("Journal of Medicinal Chemistry"), 2011; 54:7066-7083

Summary of the invention

technical problem

Under these circumstances, an object of the present invention is to provide a novel compound having an FGFR inhibitory effect or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same.

problem solution

The inventors have conducted earnest studies in view of the above circumstances, and as a result have succeeded in synthesizing a novel monocyclic pyridine derivative represented by the following formula (IA) (hereinafter referred to as the compound of the present invention (IA) )), and it has been found that such a compound has FGFR1 inhibitory action and FGFR2 inhibitory action, and thus the present invention has been accomplished. Furthermore, the inventors have found that compound (IA) of the present invention has selective inhibitory effect on FGF/FGFR signaling against VEGF/KDR signaling, in particular, selective FGFR1, FGFR2 or FGFR3 inhibitory effect.

[chemical formula 1]

Specifically, the present invention provides the following [1] to [26].

[1] A compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof:

[chemical formula 2]

in

n stands for 0 to 2;

A represents C _6-10 arylene or C _3-5 heteroarylene;

G represents a single bond, an oxygen atom or -CH ₂ -;

E represents a C _3-5 nitrogen-containing non-aromatic heterocycle;

R ¹ represents cyano, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _2-6 alkyl optionally substituted by 1 to 3 halogen atoms, optionally substituted by 1 C 1-6 alkoxy substituted by 1 to 3 halogen atoms or one hydroxy group, C _1-6 alkoxy C _{1-6 alkyl} optionally substituted by 1 to 3 halogen atoms, or optionally substituted by 1 C _1-6 alkoxy C _1-6 alkoxy substituted by 3 halogen atoms;

R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _2-6 acyl group optionally substituted by a substituent selected from the group S described below, a C ₁ optionally substituted by 1 to 3 halogen atoms _-6 alkyl, hydroxy C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms, or C _3-5 nitrogen-containing non-aromatic heterocyclic group;

R ³ represents a hydrogen atom, an oxo group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C _1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;

R ⁴ represents a C _1-6 alkyl group, with the proviso that when E represents an azetidine ring and R ² or R ³ exists on a nitrogen atom on the azetidine ring, the R ² or R ³ does not represent a hydrogen atom; and

The group S represents a group consisting of: hydroxyl, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkoxy and C _{3 -5} nitrogen-containing non-aromatic heterocyclic group.

[2] The compound according to [1] or a pharmaceutically acceptable salt thereof, represented by the following formula (IB):

[chemical formula 3]

in

n stands for 0 to 2;

A represents C _6-10 arylene or C _3-5 heteroarylene;

G represents a single bond, an oxygen atom or -CH ₂ -;

E represents a C _3-5 nitrogen-containing non-aromatic heterocycle;

R ¹ represents C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms or a hydroxyl group, or C _1-6 alkoxy C _1-6 optionally substituted by 1 to 3 halogen atoms alkoxy;

R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, a hydroxy C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C _3-5 nitrogen-containing non-aromatic heterocyclic group; and

R ³ represents a hydrogen atom, an oxo group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C _1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, The proviso is that when E represents an azetidine ring and R2 or ^R3 is present ^on a nitrogen atom on the azetidine ring, this R2 or ^R3 does not represent a ^hydrogen atom.

[3] The compound according to [1] or a pharmaceutically acceptable salt thereof, represented by the following formula (IB):

[chemical formula 4]

in

n stands for 0 to 2;

A represents C _6-10 arylene or C _3-5 heteroarylene;

G represents a single bond, an oxygen atom or -CH ₂ -;

E represents a C _3-5 nitrogen-containing non-aromatic heterocycle;

R represents C ^1-6 alkoxy optionally substituted by 1 to 3 halogen atoms or C _1-6 alkoxy C _1-6 alkoxy optionally substituted by ₁ to 3 halogen atoms;

R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, a hydroxy C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C _3-5 nitrogen-containing non-aromatic heterocyclic group; and

R ³ represents a hydrogen atom, a C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms, or a C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms, provided that when When E represents an azetidine ring and R ² or R ³ exists on a nitrogen atom on the azetidine ring, the R ² or R ³ does not represent a hydrogen atom.

[4] The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein A represents a C _1-6 arylene group.

[5] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein G represents a single bond or an oxygen atom.

[6] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein

A represents phenylene, thienylene, pyrazolylene or pyridinylene; and

E represents an azetidine ring, a pyrrolidine ring, a piperidine ring or a piperazine ring.

[7] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein

A represents phenylene; and

E represents an azetidine ring or a piperidine ring.

[8] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein

A represents phenylene; and

E represents a piperidine ring.

[9] The compound according to any one of [6] to [8] or a pharmaceutically acceptable salt thereof, wherein

n represents 0; and

G stands for single bond.

[10] The compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein

R represents C ^1-6 alkoxy or C _1-6 alkoxy C _{1-6 alkoxy} ;

R ² represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group or a hydroxy C _1-6 alkyl group; and

R ³ represents a hydrogen atom.

[11] The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, wherein R ¹ represents C _1-6 alkoxy C _1-6 alkoxy.

[12] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, represented by the following formula (II):

[chemical formula 5]

in

R ¹ represents C _1-6 alkoxy C _1-6 alkoxy; and

R ² represents a hydrogen atom, a C _1-6 alkyl group or a hydroxy C _2-6 alkyl group.

[13] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, represented by the following formula (III):

[chemical formula 6]

in

R ¹ represents C _1-6 alkoxy C _1-6 alkoxy; and

R ² represents C _1-6 alkyl or hydroxy C _2-6 alkyl.

[14] 5-((2-(4-(1-ethylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy represented by the following structural formula- N-methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof:

[chemical formula 7]

[15] 6-(2-methoxyethoxy)-N-methyl-5-((2-(4-(1-methylpiperidin-4-yl)benzyl) represented by the following structural formula Amide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof:

[chemical formula 8]

[16] 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6 represented by the following structural formula -(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof:

[chemical formula 9]

[17] 6-(2-ethoxyethoxy)-5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzyl) represented by the following structural formula Amide)pyridin-4-yl)oxy)-N-methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof:

[chemical formula 10]

[18] 6-(2-ethoxyethoxy)-5-((2-(4-(1-ethylazetidin-3-yl)benzamide) represented by the following structural formula Pyridin-4-yl)oxy)-N-methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof:

[chemical formula 11]

[19] A pharmaceutical composition comprising the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof.

[20] A therapeutic agent for gastric cancer, non-small cell lung cancer, bladder cancer, or endometrial cancer, comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [18] as an active ingredient.

[21] A method for treating gastric cancer, non-small cell lung cancer, bladder cancer, or endometrial cancer, comprising administering a pharmacologically effective dose of the compound according to any one of [1] to [18] or its pharmaceutically acceptable salt.

[22] A therapeutic agent for non-small cell lung cancer comprising the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof as an active ingredient.

[23] A therapeutic agent for squamous cell carcinoma comprising the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof as an active ingredient.

[24] An FGFR inhibitor for treating non-small cell lung cancer, comprising the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof as an active ingredient.

[25] The compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent for gastric cancer, non-small cell lung cancer, bladder cancer or endometrial cancer.

[26] The compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for gastric cancer, non-small cell lung cancer, bladder cancer or endometrial cancer use.

Beneficial effects of the present invention

As shown in the activity data obtained in the pharmacological test examples described later, the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof has FGFR1, FGFR2 and FGFR3 inhibitory effects. In addition, the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof has selective FGFR1, FGFR2 and FGFR3 inhibitory effects in direct contrast to KDR or HUVEC inhibitory effects. Therefore, the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof has potential use as a therapeutic agent for gastric cancer, non-small cell lung cancer (including lung squamous cell carcinoma), bladder cancer or endometrial cancer .

Example Description

Now, the present invention will be described in detail by defining symbols and terms used herein and explaining embodiments of the present invention and the like.

Here, the structural formula of a compound may represent a given isomer for convenience, but the compound of the present invention includes isomers (such as all geometric isomers structurally formed from the compound) , optical isomers, stereoisomers, rotamers, and tautomers based on asymmetric carbons, and mixtures of these isomers, and thus are not limited to the chemical formulas given for convenience and may is any of these isomers and mixtures. Therefore, the compound of the present invention may have one or more asymmetric carbon atoms in the molecule, and an optically active substance and a racemate may exist, and the present invention is not limited and includes all of them. However, it will be appreciated that some isomers, racemates and mixtures of isomers may exhibit greater activity than others. In addition, crystal polymorphism may exist, which does not limit the present invention, and the compound of the present invention may be in any of single crystal form, or a mixture of twin crystals or polymorphs, and the compound of the present invention includes An amorphous form and encompasses an anhydride and a solvate such as a hydrate.

The present invention includes an isotope-labeled compound of the compound (IA) of the present invention and a pharmaceutically acceptable salt thereof. The isotope-labeled compound is equivalent to the compound represented by formula (IA), except that one or more atoms are replaced by one or more atoms having an atomic mass or mass number different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, bromine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁸ F, ^35S , ^123I and ^125I .

The isotopically labeled compound, such as a compound into which a radioactive isotope such ^as3H and/ ^or14C is incorporated, is useful for tissue distribution assays of a drug and/or a substrate. The isotopes ³ H and ¹⁴ C are considered useful because these isotopes can be readily prepared and detected. The isotopes ¹¹ C and ¹⁸ F are thought to be useful in PET (Positron Emission Tomography), and the isotope ¹²⁵ I is thought to be useful in SPECT (Single Photon Emission Computed Tomography) and can be useful in brain imaging useful. Substitution by a heavier isotope such as ² H, due to its greater metabolic stability, confers some advantages in therapy, such as an increase in half-life in vivo or a reduction in the necessary dose, and is therefore considered to be useful. The isotopically labeled compounds can be similarly prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent and by carrying out the procedures as disclosed in the Schemes and/or Examples below.

The compound (IA) of the present invention can be used as a chemical probe for capturing a target protein of a biologically active low-molecular-weight compound. Specifically, one of the methods described in J.Mass Spectrum.Soc.Jpn. ("Journal of Mass Spectrometry of Japan"), Vol. 51, No. 5, 2003, pages 492-498 or WO 2007/139149 etc. A method for converting a compound of the invention into an affinity chromatography probe, a photophilic and probes etc.

Examples of labeling groups, linkers and the like used in such a chemical probe include groups belonging to the following groups (1) to (5).

(1) Protein labeling groups, such as photoaffinity labeling groups (such as benzoyl, benzophenone, azide, carbonyl azide, diaziridinyl, enone, Diazo and nitro) and chemical affinity groups (such as keto (wherein the α-carbon atom is replaced by a halogen atom), carbamoyl, ester, alkylthio, α, β-unsaturated ketone, ester or a Michael acceptor of the analogue, and an oxirane group);

(2) Cleavable linkers, such as -S-S-, -O-Si-O-, monosaccharides (such as glucosyl or galactosyl) and disaccharides (such as lactose), and oligopeptides that can be cleaved by enzymatic reactions Connector;

(3) Fishing tag groups, such as biotin and 3-(4,4-difluoro-5,7-dimethyl-4H-3a,4a-diaza-4-boron-s -benzobisinden-3-yl)propionyl;

(4) Radioactive labeling groups such as ¹²⁵ I, ³² p, ³ H and ¹⁴ C; fluorescent labeling groups such as fluorescein, rhodamine, dansyl, umbelliferone, 7-nitrofurazanyl and 3-(4,4-difluoro-5,7-dimethyl-4H-3a,4a-diaza-4-boron-s-benzobisinden-3-yl)propanoyl; chemiluminescent group such as fluorescein and luminol; and detectable markers heavy metal ions such as lanthanide metal ions and radium ions; and

(5) Groups bound to solid phase supports such as glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, and nylon beds.

A probe prepared by introducing a labeling group or the like selected from the above-mentioned groups (1) to (5) into the compound of the present invention by the method described in any of the above-mentioned documents or a similar method can be used As a chemical probe for identifying tagged proteins, the tagged protein is useful for the study of new potential drug targets.

The "halogen atom" used here refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

A "heteroatom" as used herein refers to a nitrogen atom, a sulfur atom, or an oxygen atom.

"C _1-6 alkyl" as used herein refers to a linear or branched chain alkyl group having 1 to 6 carbon atoms obtained by removing any one from an aliphatic hydrocarbon having 1 to 6 carbon atoms A monovalent group derived from a hydrogen atom. Examples of such a group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec- -Pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1 -Methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2- Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like. More precisely, it is a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or similar, and preferably methyl, ethyl or isopropyl.

The "C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms" as used herein refers to the above-mentioned C _1-6 alkyl in which any 1 to 3 hydrogen atoms may be substituted with halogen atoms. The position substituted by a halogen atom is not particularly limited, and specific examples of such a group include monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl , 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloro Ethyl, 3-fluoropropyl and the like. As the halogen atom for substitution, specifically, for example, a fluorine atom, a chlorine atom or the like is preferably used, and a fluorine atom is more preferably used.

"C _2-6 alkyl" as used herein refers to a straight chain or branched chain alkyl having 2 to 6 carbon atoms, which is obtained by removing any one from an aliphatic hydrocarbon having 2 to 6 carbon atoms A monovalent group derived from a hydrogen atom. Examples of such a group include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl , neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methyl Pentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. More precisely, it is an ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group, and is preferably ethyl.

The "C _2-6 alkyl optionally substituted with 1 to 3 halogen atoms" as used herein refers to the above-mentioned C _2-6 alkyl in which any 1 to 3 hydrogen atoms may be substituted with halogen atoms. The position substituted by a halogen atom is not particularly limited, and specific examples of such a group include 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro Ethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, and 3-fluoropropyl. As the halogen atom for substitution, specifically, for example, a fluorine atom, a chlorine atom or the like is preferably used, and a fluorine atom is more preferably used.

The "hydroxyl C _1-6 alkyl" used herein refers to the above-mentioned C _1-6 alkyl, wherein any hydrogen atom is replaced by a hydroxyl group. The position substituted by a hydroxyl group is not particularly limited, and specific examples of such a group include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1- Hydroxypropyl, 2-hydroxy-2,2-dimethylethyl and the like. Preferably it is 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2,2-dimethylethyl.

"Hydroxy C _2-6 alkyl" as used herein refers to a straight or branched chain alkyl group having 2 to 6 carbon atoms, which is obtained by removing any A monovalent group derived from one hydrogen atom, any one of which is replaced by a hydroxyl group. The position substituted by a hydroxyl group is not particularly limited, and specific examples of such a group include 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2-Hydroxy-2,2-dimethylethyl and the like. Preferably it is 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2,2-dimethylethyl.

"Hydroxy C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms" as used herein refers to the above-mentioned hydroxy C _1-6 alkyl, wherein any 1 to 3 hydrogen atoms may be replaced by halogen atoms replace. The position substituted by a halogen atom is not particularly limited. As the halogen atom to be used for substitution, specifically, for example, a fluorine atom, a chlorine atom or the like is preferably used, and a fluorine atom is more preferably used.

"C _1-6 alkoxy" as used herein refers to a "C _1-6 alkyl" defined above having an oxygen atom bonded to its terminal, and examples of such a group include methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, sec-pentoxy, Neopentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexyloxy, isohexyloxy , 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2 -Dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2 -Ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl - 2-Methylpropoxy and the like, and more precisely it is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy , n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy or the like, and preferably methoxy, ethoxy or isopropoxy.

The "C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms" as used herein refers to the above-mentioned C _1-6 alkoxy in which any 1 to 3 hydrogen atoms are substituted by halogen atoms . The position substituted by a halogen atom is not particularly limited, and specific examples of such a group include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2- Difluoroethoxy, 2,2,2-trifluoroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2-dioxyl Oxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy and the like.

The "C _1-6 alkoxy optionally substituted by 1 hydroxyl group" used herein refers to the above-mentioned C _1-6 alkoxy in which any hydrogen atom may be substituted by a hydroxyl group. The position substituted with a hydroxyl group is not particularly limited, and specific examples of such a group include 2-hydroxyethoxy, 2-hydroxypropoxy and 3-hydroxypropoxy. Preferably, it is 2-hydroxyethoxy.

The "C _1-6 alkoxy C _1-6 alkoxy" used here refers to the above-defined "C _1-6 alkoxy", wherein any hydrogen atom is replaced by the above-defined "C _{1 -6} alkoxy" substitution, and specific examples of such a group include methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, 2-methoxyethoxy, 2-methoxyethoxy, - Ethoxyethoxy, 3-methoxypropoxy and the like. Preferably, it is 2-methoxyethoxy, 2-ethoxyethoxy or 3-methoxypropoxy.

"C _1-6 alkoxy C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms" as used herein means the above-mentioned "C _1-6 alkoxy C _1-6 alkoxy group", wherein any 1 to 3 hydrogen atoms may be replaced by halogen atoms. The position substituted by a halogen atom is not particularly limited, and specific examples of such a group include fluoromethoxymethoxy, difluoromethoxymethoxy, fluoroethoxymethoxy, difluoromethoxy Ethoxymethoxy, monofluoromethoxyethoxy, trifluoromethoxyethoxy, difluoromethoxyethoxy, monofluoroethoxyethoxy, difluoroethoxyethoxy bases and the like.

The "C _1-6 alkoxy C _1-6 alkyl" used here refers to the above-defined "C _1-6 alkyl", wherein any hydrogen atom is replaced by the above-defined "C _1-6 alkoxy", and specific examples of such a group include methoxymethyl, ethoxymethyl, n-propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl , and 3-methoxypropyl. Preferably, it is methoxymethyl.

The "C _1-6 alkoxy C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms" as used herein refers to the above-mentioned C _1-6 alkoxy C _1-6 alkyl wherein any 1 to 3 hydrogen atoms in may be replaced by halogen atoms. The position substituted by a halogen atom is not particularly limited, and specific examples of such a group include monofluoromethoxymethyl, difluoromethoxymethyl, monofluoroethoxymethyl, difluoroethoxy Methyl, monofluoromethoxyethyl, trifluoromethoxyethyl, difluoromethoxyethyl, monofluoroethoxyethyl and difluoroethoxyethyl.

"Mono-C _1-6 alkylamino" as used herein refers to an amino group in which one hydrogen atom is substituted by the "C _1-6 alkyl" defined above, and specific examples of such a group include Methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, sec-pentylamino Nylamino, neopentylamino, 1-methylbutylamino, 2-methylbutylamino, 1,1-dimethylpropylamino, 1,2-dimethylpropylamino, n-hexylamino, Isohexylamino, 1-methylpentylamino, 2-methylpentylamino, 3-methylpentylamino, 1,1 _- dimethylbutylamino, 1,2-dimethylbutylamino, 2,2-Dimethylbutylamino, 1,3-Dimethylbutylamino, 2,3-Dimethylbutylamino, 3,3-Dimethylbutylamino, 1-Ethylbutyl Amino, 2-ethylbutylamino, 1,1,2-trimethylpropylamino, 1,2,2-trimethylpropylamino, 1-ethyl-1-methylpropylamino and 1 - ethyl-2-methylpropylamino, and preferably methylamino or the like.

"Di-C _1-6 alkylamino" as used herein refers to an amino group in which two hydrogen atoms are each substituted by the same or different "C _1-6 alkyl" as defined above, and such Specific examples of a group include N,N-dimethylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino, N,N -Di-n-butylamino, N,N-di-isobutylamino, N,N-di-sec-butylamino, N,N-di-tert-butylamino, N-ethyl-N-methyl Amino, N-n-propyl-N-methylamino, N-isopropyl-N-methylamino, N-n-butyl-N-methylamino, N-isobutyl-N-methylamino, N-sec-butyl-N-methylamino and N-tert-butyl-N-methylamino, and preferably N,N-dimethylamino or the like.

The " _C2-6 acyl group" used herein refers to a group containing an atomic group obtained by excluding an OH group from a carboxyl group of an aliphatic carboxylic acid having 2 to 6 carbon atoms, and such a group Specific examples include acetyl, propionyl and butyryl.

The "oxo group" used here means a substituent in which one oxygen atom is bonded to a carbon atom or a nitrogen atom, and a specific example of a structure in which one oxygen atom is bonded to a carbon atom A carbonyl group is included, and specific examples of groups in which one oxygen atom is bonded to one nitrogen atom include N-oxides.

The "C _3-5 heteroarylene group" as used herein refers to a divalent group having 3 to 5 carbon atoms forming a ring formed from a hetero having 1 to 2 atoms forming the ring atom produced by removal of any two hydrogen atoms in a heteroaromatic compound, and specific examples of such a group include furylylene, thienylene, pyrrolylene, imidazolyl, thiazolyl, Pyrazolyl, oxazolylene, isoxazolylene, isothiazolylene, furazanylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene and the like, and it is preferably is pyridylene, pyrazolylene or thienylene.

The "C _3-5 nitrogen-containing non-aromatic heterocyclic group" used herein means a monovalent group having 3 to 5 carbon atoms forming a ring and 1 to 2 nitrogen atoms among the atoms forming the ring non-aromatic ring group, and specific examples of such a group include azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, isoxazolidinyl , isothiazolidinyl, morpholinyl, thiomorpholinyl, and the like.

The "C _3-5 nitrogen-containing non-aromatic heterocyclic ring" used herein refers to a non-aromatic heterocyclic ring having 3 to 5 carbon atoms forming the ring and 1 to 2 nitrogen atoms among the atoms forming the ring. and specific examples of such a group include azetidine ring, pyrrolidine ring, pyrazolidine ring, imidazolidine ring, piperidine ring, piperazine ring, isoxazolidine ring, isothiazolidine ring, ring, morpholine ring, thiomorpholine ring, and the like.

The "C _6-10 arylene group" used herein means a divalent group generated by removing any two hydrogen atoms from an aromatic hydrocarbon having 6 to 10 carbon atoms, and such a Specific examples of the group include phenylene, naphthylene, indenylene, azulenylene, heptenylene and the like, and it is preferably phenylene.

In the chemical formulas used herein, n represents 0 to 2. Preferably, n is 0 or 1, and more preferably, n is 0.

In the formula used here, A represents C _6-10 arylene or C _3-5 heteroarylene, preferably phenylene, thienylene, pyridinylene or pyrazolylene, and more preferably Ground is phenylene.

In the formula used here, G represents a single bond, an oxygen atom or -CH ₂ -, preferably a single bond or an oxygen atom, and more preferably a single bond.

In the formula used here, E represents the above-mentioned C _3-5 nitrogen-containing non-aromatic heterocyclic ring, and is exactly, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring or A piperazine ring, preferably an azetidine ring or a piperidine ring, and more preferably a piperidine ring.

In the formula used here, R ¹ represents cyano, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _2-6 optionally substituted by 1 to 3 halogen atoms Alkyl, C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms or a hydroxy group, C _1-6 alkoxy C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms group, or C _1-6 alkoxy C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms. Preferably, it is a C _1-6 alkoxy or a C _1-6 alkoxy C _1-6 alkoxy. Specific examples of such a group include cyano, methylamino, N,N-dimethylamino, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, iso Propoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy Fluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 3-fluoropropoxy, 2-hydroxyethoxy, methoxymethyl, ethoxymethyl, n-propyl Oxymethyl, ethoxymethoxy, n-propoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, monofluoromethyl Oxymethoxy, difluoromethoxymethoxy, fluoroethoxymethoxy, difluoroethoxymethoxy, fluoromethoxyethoxy, difluoromethoxyethoxy , trifluoromethoxyethoxy, monofluoroethoxyethoxy and difluoroethoxyethoxy. Preferred examples include cyano, N,N-dimethylamino, ethyl, methoxy, ethoxy, isopropoxy, 3-fluoropropoxy, 2-hydroxyethoxy, methoxymethyl 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy, where methoxy, 2-methoxyethoxy, 2-ethoxyethoxy and the like are preferred, and 2-methoxyethoxy and 2-ethoxyethoxy are more preferred.

In the ^formula used herein, R represents a hydrogen atom, a halogen atom, a hydroxyl group, a C2-6 acyl group optionally substituted by a substituent selected from the group S, a _C2-6 acyl group optionally substituted by 1 C _1-6 alkyl substituted by up to 3 halogen atoms, a hydroxy C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms, or a C _3-5 nitrogen-containing non-aromatic heterocyclic group . Here, the group S represents a group consisting of the following: a hydroxyl group, a mono-C _1-6 alkylamino group, a di-C _1-6 alkylamino group, a C _{1-6 6} alkoxy groups and a C _3-5 nitrogen-containing non-aromatic heterocyclic group. Preferably, it is a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group or a hydroxy C _1-6 alkyl group, or more preferably, it is a hydrogen atom, a hydroxy group, a C _1-6 alkyl group or a hydroxy C _{1 -6} alkyl. Specific examples of R include ^hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, Butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, monochloromethyl, di Oxymethyl, trichloroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl , 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2-hydroxy-2,2-dimethylethyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl. Preferably, it is hydrogen atom, fluorine atom, hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2 -hydroxypropyl, 1-hydroxypropyl, 2-hydroxy-2,2-dimethylethyl, azetidinyl, pyrrolidinyl, or piperidinyl, and more preferably, it is methyl , ethyl or 2-hydroxyethyl.

In the formula used here, R ³ represents a hydrogen atom, an oxo group, a C 1-6 alkyl optionally substituted by 1 to 3 halogen atoms, or a C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms C _1-6 alkoxy. Preferably, it is a hydrogen atom, C _1-6 alkyl or C _1-6 alkoxy. Specifically, it is preferably a hydrogen atom, a methyl group or an ethyl group, and more preferably a hydrogen atom.

In the formula used here, R ⁴ represents C _1-6 alkyl. Preferably it is methyl.

However, if E represents an azetidine ring and R2 or ^R3 is present ^on a nitrogen atom of the azetidine ring, this R2 or ^R3 does not represent a ^hydrogen atom. In addition, each of R ² and R ³ is an atom or group substituted at any position on E (that is, any position on the C _3-5 nitrogen-containing non-aromatic heterocyclic ring).

In the following formula (IB),

[chemical formula 12]

The partial structure represented by the following chemical formula (IV) is preferably a partial structure represented by the following chemical formula (V) or (VI), and more preferably a partial structure represented by chemical formula (V).

[chemical formula 13]

[chemical formula 14]

[chemical formula 15]

In formula (V), R ² represents a hydrogen atom, C _1-6 alkyl or hydroxy C _2-6 alkyl, and specific examples include hydrogen atom, methyl, ethyl, propyl, isopropyl, 2- Hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2,2-dimethylethyl and the like. It is preferably methyl, ethyl, 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2,2-dimethylethyl.

In formula (VI), R ² represents C _1-6 alkyl or hydroxy C _2-6 alkyl, and specific examples include methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 3- Hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2,2-dimethylethyl and the like. It is preferably methyl, ethyl, 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2,2-dimethylethyl.

A compound of the present invention is preferably any one of the following compounds or analogs or a pharmaceutically acceptable salt thereof:

5-((2-(4-(1-ethylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole -1-formamide;

6-(2-methoxyethoxy)-N-methyl-5-((2-(4-(1-methylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy base)-1H-indole-1-carboxamide;

5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy Base)-N-methyl-1H-indole-1-carboxamide;

6-(2-Ethoxyethoxy)-5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy Base)-N-methyl-1H-indole-1-carboxamide;

6-(2-Ethoxyethoxy)-5-((2-(4-(1-ethylazetidin-3-yl)benzamide)pyridin-4-yl)oxy) -N-Methyl-1H-indole-1-carboxamide.

Examples of a "salt" used here include salts of inorganic acids, salts of organic acids, and salts of acidic amino acids, and in particular, pharmaceutically acceptable salts are preferred. Additionally, a salt of a compound of the present invention encompasses an anhydride of a pharmaceutically acceptable salt thereof as well as a solvate such as a hydrate of the pharmaceutically acceptable salt.

Preferable examples of salts of inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like, and preferable examples of salts of organic acids include acetates, succinates, fumarates , maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, ethanesulfonate, p-toluenesulfonate and the like.

Preferable examples of salts of acidic amino acids include aspartate and glutamate, and the like.

The compound (IA) of the present invention or a pharmaceutically acceptable salt thereof can be formulated by a common method, and the dosage form can be, for example, an oral preparation (such as tablet, granule, powder, capsule, syrup or the like), Preparations for injection (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration or the like), or preparations for external use (such as percutaneously absorbable drugs (including ointments, patches and the like) ), eye drops, nose drops, suppositories or the like).

To produce an oral solid preparation, if necessary, a vehicle, a binder, a disintegrating agent, a lubricant, a coloring agent, etc. may be added to the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof, and passed through a The resulting mixture is prepared into tablets, granules, powders, or capsules by conventional methods. In addition, tablets, granules, powders, capsules and the like can be film-coated if necessary.

Examples of vehicles include lactose, corn starch, crystalline cellulose, etc., examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, etc., examples of disintegrants include carboxymethyl cellulose calcium, cross-linked Carmellose sodium, etc., examples of the lubricant include magnesium stearate, calcium stearate, etc., examples of the coloring agent include titanium oxide, etc., and examples of the coating agent include hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. base cellulose, methyl cellulose, etc., but these components are not limited to the above examples.

The solid formulations such as tablets, capsules, granules or powders may contain the compound (IA) or its pharmaceutically acceptable salt.

To produce an injection preparation (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration or the like), if necessary, compound (IA) of the present invention or its pharmaceutically acceptable pH adjusters, buffers, suspending agents, solubilizers, antioxidants, preservatives (fungicides), tonicity adjusters, etc. are added to the salt, and the resulting mixture can be prepared into an injection formulation by a conventional method. Furthermore, the resultant can be freeze-dried to be used as a freeze-dried product to be dissolved before use.

Examples of pH adjusters and buffers include organic or inorganic acids and/or pharmaceutically acceptable salts thereof, examples of suspending agents include methylcellulose, polysorbate 80, sodium carboxymethylcellulose and the like Examples of solubilizers include polysorbate 80, polyethylene oxide sorbitan monolaurate and the like, examples of antioxidants include α-tocopherol and the like, examples of preservatives include p-hydroxybenzoic acid methyl ester, ethyl p-hydroxybenzoate and the like, and examples of the tonicity adjusting agent include glucose, sodium chloride, mannitol and the like; however, these components are not limited to the above examples.

Such an injection formulation may contain the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof in an amount of usually 0.000001% to 99.5% by weight, and particularly 0.00001% to 90% by weight.

To produce a preparation for external use, a base material is added to the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof, and if necessary, such as the above-mentioned preservatives, stabilizers, pH adjustment, etc. agents, antioxidants, coloring agents and the like, and prepare the mixture by a conventional method into, for example, percutaneously absorbable drugs (such as ointments or patches), eye drops, nasal drops, suppositories or analog.

As the base material to be used, various materials commonly used in, for example, pharmaceuticals, quasi-drugs, and cosmetics can be used. Specific examples of the material include animal and vegetable oils, mineral oils, ester oils, waxes, emulsifiers, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyols, water-soluble polymers, clay minerals, purified water Wait.

Such an external preparation may contain the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof in an amount of usually 0.000001% to 99.5% by weight, and particularly 0.00001% to 90% by weight.

The dose of the compound (IA) of the present invention or a pharmaceutically acceptable salt thereof depends on the severity of the symptoms, the age, sex and body weight of the patient, the form of administration and the type of salt, the specific type of disease, etc., and is not particularly limited unless Exceeds the maximum dose of the medicament that can be given without causing unacceptable adverse reactions, and in adult patients, it is at dosages of usually about 30 μg to 10 g, specifically 100 μg to 5 g and more specifically 100 μg to 1 g It is administered once a day or several times a day respectively in a dose for oral administration or in a dose for injection administration usually about 30 μg to 1 g, specifically 100 μg to 500 mg, and more specifically 100 μg to 300 mg.

[General Synthetic Method]

A production method of the compound (IA) used in the present invention will now be described. The compound (IA) of the present invention can be synthesized by using general organic synthesis means, and some examples of the compound (IA) of the present invention are compounds (1-1), (1-2), (1-3), (1 -4), (1-5), (1-6), (1-7), (1-8), (1-9) and (1-10) can be produced by the following [production method 1 ] and so on in the method synthesis. If a protecting group is used in the production method described here, known protecting groups can be appropriately selected and introduced, for example in Green (Green) PROTECTIVE GROUP IN ORGANICCHEMISTRY ("Protective Groups in Organic Chemistry") "), Fourth Edition, JOHN WILEY & SONS, INC. (John Wiley International Publishing Company), and may be suitably deprotected by known methods.

[production method 1]

Representative production method of compound (IA) used in the present invention

[chemical formula 16]

Wherein R ¹ , R ² , R ³ , A, E, G and n represent the same as defined above.

[Production method 1-1]

Production method for compound (1-1), (1-2), (1-3), (1-6) or (1-7)

[chemical formula 17]

In the above formula, R ¹ , R ³ (excluding oxo group), R ⁴ , A, E, G and n represent the same as defined above; R ^2a and R ^2b each represent a hydrogen atom, optionally C _1-5 alkyl optionally substituted by 1 to 3 halogen atoms, or hydroxy C _1-5 alkyl optionally substituted by 1 to 3 halogen atoms; R ^2c and R ^2d each represent a hydrogen atom or optionally C _1-4 alkyl optionally substituted by 1 to 3 halogen atoms; R ^2e represents C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms, or optionally substituted by 1 to 3 halogen atoms Substituted hydroxy C _1-6 alkyl, if R ^2e has a hydroxy group, the hydroxy group can be protected by a known suitable protecting group; X ¹ represents a halogen atom such as chlorine atom, bromine atom, or iodine atom, or sulphon R ^2f represents a C _1-5 alkyl optionally substituted by C _1-6 alkoxy; R ^2g represents a hydroxyl, mono- C _1-6 alkylamino or C _1-5 alkyl optionally substituted by di-C _1-6 alkylamino, if R ^2g has hydroxyl or mono-C _1-6 alkylamino, the hydroxyl or the Mono-C _1-6 alkylamino can be protected by a known suitable protecting group.

Compound (2) can also be produced by the production examples described in any of the following examples, the method in [Production method 2] or a similar method.

Compounds (2A), (2B), (2C), (2D) and (2E) may be commercially available products, or may be produced from commercially available products by known methods. Alternatively, these compounds can be produced by the methods described in Production Examples in any of the Examples below or by similar methods. Compound (2A) may be in any form ranging from a dimer to a multimer.

[Process 1-1-1]

In this process, compound (2) and compound (2A) are reacted with each other in the presence of a reducing agent to give a compound (1-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol, a nitrile solvent can be used such as acetonitrile, a carboxylic acid solvent such as acetic acid, an aromatic hydrocarbon solvent such as benzene or toluene, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, a halogenated hydrocarbon solvent such as dichloro Methane or chloroform, water, or a mixed solvent of these. As a reducing agent used in this reaction, a metal hydride complex such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or a substituted borane such as diborane or a A pyridine borane complex. Alternatively, a catalytic reduction catalyst such as palladium-carbon may be used under a hydrogen atmosphere. Compound (2A) can be used in an amount of 1 to 10 equivalents to compound (2), and is preferably used in an amount of 1 to 2 equivalents. The reducing agent can be used in an amount of 1 equivalent or more to compound (2), and is preferably used in an amount of 1 to 5 equivalents. In this reaction, an acid such as acetic acid can be added in an amount of 0 to 10 equivalents. The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 1-1-2]

In this process, compound (2) reacts with compound (2B) to give a compound (1-2). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol, an amide solvent can be used such as N,N-dimethylformamide or N-methylpyrrolidone, a nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, or one of these a mixed solvent. In this reaction, an alkylamine such as triethylamine, an aromatic amine such as pyridine, or an inorganic base such as potassium carbonate can be used as a base. Compound (2B) can be used in an amount of 1 equivalent or more to compound (2), and is preferably used in an amount of 1 to 10 equivalents. The base can be used in an amount of 0 to 10 equivalents to compound (2). The reaction temperature is from 0°C to 200°C, and the reaction time is from 10 minutes to 24 hours.

[Process 1-1-3]

In this process, compound (2) reacts with compound (2C) to give a compound (1-3). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, a nitrile solvent such as acetonitrile, an aromatic A hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, dimethylsulfoxide, or a mixture of these solvent. In this reaction, an alkylamine such as triethylamine, an aromatic amine such as pyridine, or an inorganic base such as sodium bicarbonate, potassium carbonate or cesium carbonate can be used as a base. Compound (2C) can be used in an amount of 1 equivalent or more to compound (2), and is preferably used in an amount of 1 to 3 equivalents. The base can be used in an amount of 1 to 10 equivalents to compound (2). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. If the hydroxyl group of R ^2e is protected, it can be deprotected by known methods.

[Process 1-1-4]

In this process, compound (2) reacts with compound (2D) to give compound (1-6). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, a A nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or these a mixed solvent. In this reaction, an alkylamine such as triethylamine, an aromatic amine such as pyridine, or an inorganic base such as sodium bicarbonate, potassium carbonate or cesium carbonate can be used as a base. Compound (2D) can be used in an amount of 1 equivalent or more to compound (2), and is preferably used in an amount of 1 to 3 equivalents. The base can be used in an amount of 1 to 10 equivalents to compound (2). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 1-1-5]

In this process, compound (2) and compound (2E) react with each other by using a condensing agent to give compound (1-7). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, an A nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, a condensing agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. In addition, 1-hydroxybenzotriazole or the like may be used as an additive. In this reaction, an alkylamine such as triethylamine or N,N-diisopropylethylamine, an aromatic amine such as 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate or cesium carbonate can be used as A single base, or a combination of these bases may be used. Compound (2E) can be used in an amount of 1 equivalent or more to compound (2), and is preferably used in an amount of 1 to 3 equivalents. The condensing agent can be used in the same amount as compound (2E), and the base can be used in an amount of 1 to 10 equivalents to compound (2). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. If R ^2g is protected by a hydroxyl group or a mono-C _1-6 alkylamino group, it can be deprotected by known methods.

[Production method 1-2]

Production method for compound (1-4)

[chemical formula 18]

In the above formula, R ¹ , R ² , R ³ , R ⁴ , A, E, G and n represent the same as defined above; and X ² represents a halogen atom such as a chlorine atom or a bromine atom, or a sulfur A leaving group of an acid salt such as methanesulfonate or p-toluenesulfonate.

Compounds (3) and (4) can also be produced by the method described in [Production method 3], the production example in any of the following examples, or a similar method.

Compounds (3A) and (4-1) may be commercially available products, or may be produced from commercially available products by known methods. Alternatively, these compounds can be produced by the methods described in [Production Method 6], Production Examples in any of the following examples, or similar methods.

[Process 1-2-1]

In this process, compound (4) reacts with compound (4-1) to give compound (3). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, an A nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or these a mixed solvent. In this reaction, an alkylamine such as triethylamine or N,N-diisopropylethylamine, an aromatic amine such as 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate or cesium carbonate can be used as A single base, or a combination of these bases may be used. Compound (4-1) can be used in an amount of 1 equivalent or more to compound (4), and is preferably used in an amount of 2 to 3 equivalents. The base can be used in an amount of 1 to 10 equivalents to compound (4). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. In this process, a diacyl form generated from one reaction of 2 equivalents of compound (4-1) can be produced, and this can be used directly in the following reaction.

[Process 1-2-2]

In this process, compound (3) reacts with compound (3A) to give a compound (1-4). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene, a A halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, dimethylsulfoxide, or a mixed solvent of these. In this reaction, an alkylamine such as triethylamine or N,N-diisopropylethylamine, or an inorganic base such as potassium carbonate or cesium carbonate can be used as a base. Compound (3A) can be used in an amount of 1 equivalent or more to compound (3), and is preferably used in an amount of 1 to 10 equivalents. The base can be used in an amount of 1 to 10 equivalents to compound (3). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production method 1-3]

Production method for compound (1) or (1-5)

[chemical formula 19]

In the above formula, R ¹ , R ² , R ³ , R ⁴ , A, E, G and n represent the same as defined above; X ³ represents a halogen atom such as a chlorine atom or a bromine atom; and Pro ¹ represents Known protecting groups for nitrogen atoms such as tert-butoxycarbonyl.

The compound (4) can be produced by the method described in the production example of any of the following examples, [Production method 3] or a similar method.

Compounds (4-2), (4-3), (4-4) and (4-5) may be commercially available products, or may be produced from commercially available products by known methods. These compounds can also be produced by the methods described in [Production Method 5], Production Examples in any of the following examples, or similar methods.

[Process 1-3-1 or 1-3-3]

In this process, compound (4) reacts with compound (4-2) or (4-4) to give compound (1) or (1-5), respectively. The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, an A nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or these a mixed solvent. In this reaction, an alkylamine such as triethylamine or N,N-diisopropylethylamine, an aromatic amine such as 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate or cesium carbonate can be used as A single base, or a combination of these bases may be used. Compound (4-2) or (4-4) can be used in an amount of 1 equivalent or more to compound (4), and is preferably used in an amount of 2 to 3 equivalents. The base can be used in an amount of 1 to 10 equivalents to compound (4). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. In this process, a diacyl form resulting from a reaction of 2 equivalents of compound (4-2) or (4-4) can be produced. In this case the diacyl form can be converted to a desired monoacyl form by treatment with ammonia or a primary or secondary alkyl amine such as methylamine or piperidine.

In the process 1-3-3, the protecting group for the nitrogen atom can then be removed by a known method. If Pro ¹ is, for example, tert-butoxycarbonyl, it can be achieved by using a solvent that does not inhibit the reaction such as a halogenated hydrocarbon solvent such as dichloromethane, an ester solvent such as ethyl acetate, an alcohol solvent such as methanol , or a mixed solvent of these and the deprotection is carried out by using an acid such as trifluoroacetic acid or hydrochloric acid.

[Process 1-3-2 or 1-3-4]

In this process, compound (4) and compound (4-3) or (4-5) are reacted with each other by using a condensing agent to give compound (1) or (1-5). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, an A nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, a condensing agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. In addition, 1-hydroxybenzotriazole or the like may be used as an additive. In this reaction, an alkylamine such as triethylamine or N,N-diisopropylethylamine, an aromatic amine such as 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate or cesium carbonate can be used as A single base, or a combination of these bases may be used. Compound (4-3) or (4-5) can be used in an amount of 1 equivalent or more to compound (4), and is preferably used in an amount of 2 to 3 equivalents. The condensing agent can be used in the same amount as the compound (4-3) or (4-5), and the base can be used in the amount of 1 to 10 equivalents to the compound (4). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. In this process, a diacyl form resulting from a reaction of 2 equivalents of compound (4-3) or (4-5) can be produced. In this case, the diacyl form can be converted to a desired monoacyl form by treatment with ammonia or a primary or secondary alkyl amine such as methylamine or piperidine. If ^R2 is protected with a known protecting group, the protecting group is deprotected by known methods.

In the process 1-3-4, the protecting group for the nitrogen atom can then be removed by a known method. If Pro ¹ is, for example, tert-butoxycarbonyl, it can be achieved by using a solvent that does not inhibit the reaction such as a halogenated hydrocarbon solvent such as dichloromethane, an ester solvent such as ethyl acetate, an alcohol solvent such as methanol , or a mixed solvent of these and the deprotection is carried out by using an acid such as trifluoroacetic acid or hydrochloric acid.

[Production method 1-4]

Production method for compound (1-8)

[chemical formula 20]

In the above formula, R ¹ , R ² , R ⁴ , A, E, G and n represent the same as defined above.

Compound (1-1-1) can also be produced by the production examples described in any of the following examples, the method in [Production method 1-1] or a similar method.

[Process 1-4]

In this process, compound (1-1-1) interacts with an oxidizing agent to give compound (1-8). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, a halogenated hydrocarbon solvent such as dichloromethane or chloroform, an alcohol solvent such as Methanol or t-butanol, an organic acid such as acetic acid, or a mixed solvent of these. In this reaction, hydrogen peroxide, an organic peroxide, or an organic peroxyacid such as 3-chloroperoxybenzoic acid can be used as the oxidizing agent. The oxidizing agent can be used in an amount of 0.5 to 10 equivalents relative to compound (1-1-1). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production method 1-5]

Production method for compound (1-10)

[chemical formula 21]

In the above formula, R ² , R ⁴ , A, E, G, and n represent the same as defined above; and m represents an integer of 2 to 6.

Compound (1-9) can also be produced by the production examples described in any of the following examples, the method in [Production Method 1-1], [Production Method 1-2], [Production Method 1-3] or the like in production.

[Process 1-5]

In this process, compound (1-9) interacts with boron tribromide to give compound (1-10). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example a halogenated hydrocarbon solvent such as dichloromethane or chloroform can be used. Boron tribromide used in this reaction can be used in an amount of 1 to 10 equivalents relative to compound (1-9). The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[production method 2]

Production method for compound (2)

[chemical formula 22]

In the above formula, R ¹ , R ³ , R ⁴ , A, E, G and n represent the same as defined above; X ³ represents a halogen atom such as a chlorine atom or a bromine atom; and Pro ¹ represents a Known protecting groups on the nitrogen atom such as tert-butoxycarbonyl.

Compounds (4-6) and (4-7) may be commercially available products, or may be produced from commercially available products by known methods. These compounds can also be produced by the methods described in Production Examples in any of the Examples below or by similar methods. Compound (4-6) can also be produced by the method described in [Production Method 5] or a similar method.

[Procedure 2-1]

In this process, compound (4) reacts with compound (4-6) to give compound (2). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, an A nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or these a mixed solvent. In this reaction, an alkylamine such as triethylamine or N,N-diisopropylethylamine, an aromatic amine such as 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate or cesium carbonate can be used as A single base, or a combination of these bases may be used. Compound (4-6) can be used in an amount of 1 equivalent or more to compound (4), and is preferably used in an amount of 2 to 3 equivalents. The base can be used in an amount of 1 to 10 equivalents to compound (4). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. In this process, a diacyl form from a reaction of 2 equivalents of compound (4-6) can be produced. In this case the diacyl form can be converted to a desired monoacyl form by treatment with ammonia or a primary or secondary alkyl amine such as methylamine or piperidine. The protecting group for the nitrogen atom can subsequently be removed by known methods. If Pro ¹ is, for example, tert-butoxycarbonyl, it can be achieved by using a solvent that does not inhibit the reaction such as a halogenated hydrocarbon solvent such as dichloromethane, an ester solvent such as ethyl acetate, an alcohol solvent such as methanol , or a mixed solvent of these and the deprotection is carried out by using an acid such as trifluoroacetic acid or hydrochloric acid.

[Procedure 2-2]

In this process, compound (4) reacts with compound (4-7) to give compound (2). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, an A nitrile solvent such as acetonitrile, an aromatic hydrocarbon solvent such as toluene, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, a condensing agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. In addition, 1-hydroxybenzotriazole or the like may be used as an additive. In this reaction, an alkylamine such as triethylamine or N,N-diisopropylethylamine, an aromatic amine such as 4-dimethylaminopyridine, or an inorganic base such as potassium carbonate or cesium carbonate can be used as A single base, or a combination of these bases may be used. Compound (4-7) can be used in an amount of 1 equivalent or more to compound (4), and is preferably used in an amount of 2 to 3 equivalents. The base can be used in an amount of 1 to 10 equivalents to compound (4). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. In this procedure, a diacyl form from a reaction of 2 equivalents of compound (4-7) can be produced. In this case the diacyl form can be converted to a desired monoacyl form by treatment with ammonia or a primary or secondary alkyl amine such as methylamine or piperidine. The protecting group for the nitrogen atom can subsequently be removed by known methods. If Pro ¹ is, for example, tert-butoxycarbonyl, it can be achieved by using a solvent that does not inhibit the reaction such as a halogenated hydrocarbon solvent such as dichloromethane, an ester solvent such as ethyl acetate, an alcohol solvent such as methanol , or a mixed solvent of these and the deprotection is carried out by using an acid such as trifluoroacetic acid or hydrochloric acid.

[production method 3]

Production method for compound (4)

[chemical formula 23]

In the above formula, what R ¹ and R ⁴ represent is the same as defined above; Pro ² represents a protecting group for a nitrogen atom such as acetyl; Pro ³ represents a protecting group for a phenolic oxygen atom such as benzyl; and X ³ represents a halogen atom such as a chlorine atom or a bromine atom.

Compounds (7), (8), (9), (10) and (11) may be commercially available products, or may be produced from commercially available products by known methods. These compounds can also be produced by the methods described in Production Examples in any of the Examples below. Compounds (5) and (6) can also be produced by the methods described in Production Examples in any of the Examples below or by similar methods.

Compounds (5A), (6A) and (11A) may be commercially available products, or may be produced from commercially available products by known methods. Alternatively, these compounds can be produced by the method described in the production examples of any of the examples below or by a similar method.

[Procedure 3-1]

In this process, compound (11) reacts with compound (11A) to give compound (10). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol, a nitrile solvent can be used such as acetonitrile, a ketone solvent such as acetone, a halogenated hydrocarbon solvent such as methylene chloride, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, dimethyl sulfoxide, or a combination of these a mixed solvent. In this reaction, compound (11A) is used in an amount of 1 to 5 equivalents to compound (11), and 1 to 5 equivalents of a base such as sodium bicarbonate, potassium carbonate, sodium methoxide, sodium hydride or diiso Propylethylamine. In addition, sodium iodide or potassium iodide may be added as an additive. The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 3-2]

In this process, compound (10) interacts with nitromethane to give compound (9). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an alcohol solvent such as methanol, an organic acid solvent such as acetic acid, or a combination of these can be used a mixed solvent. In this reaction, nitromethane is used in an amount of 1 to 10 equivalents, and 0.1 to 10 equivalents of ammonium acetate, ethylenediamine-N,N'-diacetic acid or the like may be added as an additive. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 100 hours.

[Process 3-3]

In this process, compound (9) is nitrated to give compound (8). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, a halogenated hydrocarbon solvent such as dichloromethane, an organic acid solvent such as acetic acid can be used , sulfuric acid, or a mixed solvent of these. In this reaction, fuming nitric acid, concentrated nitric acid, or nitric acid is used, and acetic anhydride or the like may be added as an additive. Nitric acid and the like used in this reaction may be in an amount of 1 to 100 equivalents to compound (9). The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 100 hours.

[Process 3-4]

In this process, compound (8) is cyclized to give compound (7). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol, an aromatic A hydrocarbon solvent such as benzene or toluene, a hydrocarbon solvent such as cyclohexane, water, or a mixed solvent of these. In this reaction, a heavy metal such as iron or zinc is used, and an acid such as acetic acid, a salt such as ammonium chloride, a base such as sodium hydroxide, an inorganic compound such as silica gel or a combination of these may be added. mixture as an additive. The heavy metal such as iron used in this reaction may be in an amount of 5 to 20 equivalents to compound (8). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 3-5]

In this procedure, Pro ³ of compound (7) is deprotected to give compound (6). Pro ³ can be deprotected by a known method, and if Pro ³ is benzyl, the solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and can be For example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol, an aromatic hydrocarbon solvent such as benzene or toluene, acetic acid, water, or a mixed solvent of these is used. This reaction can be carried out under a hydrogen atmosphere using a catalytic reduction catalyst such as palladium-carbon as a catalyst. The pressure of the hydrogen can be from normal pressure to 20 atm, and the catalyst can be used in an amount of 0.001 to 1 equivalent to the compound (7). Additionally, an acid such as hydrochloric acid may be added. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 3-6]

In this process, compound (8) is cyclized to give compound (6). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as methanol, an aromatic Hydrocarbon solvents such as benzene or toluene, acetic acid, water, or a mixed solvent of these. This reaction can be carried out under a hydrogen atmosphere using a catalytic reduction catalyst such as palladium-carbon as a catalyst. The pressure of the hydrogen can be from normal pressure to 20 atm, and the catalyst can be used in an amount of 0.001 to 1 equivalent to the compound (8). An acid such as hydrochloric acid may be added as an additive. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 3-7]

In this process, compound (6) reacts with compound (6A) to give compound (5). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example an amide solvent such as N,N-dimethylformamide or N-formaldehyde can be used pyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, a base such as potassium carbonate, cesium carbonate or potassium tert-butoxide can be used as a base. The base can be used in an amount of 1 to 10 equivalents to compound (6), and is preferably used in an amount of 1 to 2 equivalents. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Deprotection of Pro ² can be carried out by known methods, and if Pro ² is acetyl, it can be obtained by using a solvent that does not inhibit the reaction such as an alcoholic solvent such as methanol and by using a base such as potassium carbonate, hydroxide Sodium or sodium methoxide is used for deprotection, or it can be deprotected by using a solvent that does not inhibit the reaction such as an ether solvent such as 1,4-dioxane and by using an acid such as hydrochloric acid. Alternatively, the process can be performed by using a compound not protected by Pro ² such as compound (6A).

[Process 3-8]

In this process, compound (5) reacts with compound (5A) to give compound (4). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an amide solvent such as N,N-dimethyl methyl formamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, a base such as sodium hydroxide or potassium tert-butoxide can be used as a base. Compound (5A) can be used in an amount of 1 equivalent or more to compound (5), and is preferably used in an amount of 1 to 2 equivalents. The base can be used in an amount of 1 to 2 equivalents to compound (5). The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[production method 4]

Production method for compound (11-1)

[chemical formula 24]

In the above formula, R ^1a represents C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms, or C _1-6 alkoxy C _1-6 optionally substituted by 1 to 3 halogen atoms ₆ alkyl; and X ³ represents a leaving group of a halogen atom such as a bromine atom or an iodine atom.

Compound (12) may be a commercially available product, or may be produced from a commercially available product by a known method.

Compound (12A) may be a commercially available product, or may be produced from a commercially available product by a known method.

[Procedure 4-1]

In this process, compound (12) reacts with compound (12A) to give a compound (11-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol, a nitrile solvent can be used Such as acetonitrile, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, compound (12A) is used in an amount of 0.5 to 1.5 equivalents to compound (12), and 0.5 to 1.5 equivalents of a base such as sodium bicarbonate, potassium carbonate, sodium methoxide or sodium hydride may be added as an additive. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 100 hours.

[production method 5]

Production method for compound (4-2), (4-4) or (4-6)

[chemical formula 25]

In the above formula, R ² , R ³ , A, E, G and n represent the same as defined above; X ³ represents a halogen atom such as chlorine atom or bromine atom; and Pro ¹ represents a nitrogen atom Known protecting groups such as tert-butoxycarbonyl.

Compounds (4-3), (4-5) and (4-7) may be commercially available products, or may be produced from commercially available products by known methods. Alternatively, these compounds can also be produced by the methods described in Production Examples in any of the following Examples or the methods described in [Production Method 7], [Production Method 9] or similar methods.

[Process 5-1, 5-2 or 5-3]

In this process, compound (4-3), (4-5) or (4-7) is reacted to give compound (4-2), (4-4) or (4-6), respectively. The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, a halogenated hydrocarbon solvent such as dichloromethane, an ether solvent such as tetrahydrofuran, A nitrile solvent such as acetonitrile, or a mixed solvent of these. In this reaction, an acid halide such as oxalyl chloride or an inorganic halogen compound such as thionyl chloride is used in an amount of 1 to 10 equivalents to compound (4-3), (4-5) or (4-7), And 1 to 10 equivalents of a base such as benzotriazole may be added as an additive. In addition, a catalytic amount of N,N-dimethylformamide, N-methylpyrrolidone or the like can be added. The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[production method 6]

Production method for compound (4-1)

[chemical formula 26]

In the above formula, A, G and n represent the same as defined above; m represents 0 or 1; and X ³ represents a halogen atom such as a chlorine atom or a bromine atom.

Compounds (4AA), (4AB) and (4B) may be commercially available products, or may be produced from commercially available products by known methods. Alternatively, these compounds can be produced by the methods described in Production Examples in any of the Examples below or by similar methods.

[Procedure 6-1]

In this process, compound (4AA) is reacted to give compound (4AB). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an alcohol solvent such as ethanol, or one of these can be used a mixed solvent. In this reaction, a reducing agent such as sodium borohydride can be used in an amount of 1 to 10 equivalents to compound (4AA). The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 6-2 or 6-3]

In this process, compound (4AB) or compound (4B) is reacted to give compound (4-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, a halogenated hydrocarbon solvent such as dichloromethane, an ether solvent such as tetrahydrofuran, A nitrile solvent such as acetonitrile, or a mixed solvent of these. In this reaction, an acid halide such as oxalyl chloride or an inorganic halogen compound such as thionyl chloride can be used in an amount of 1 to 10 equivalents to compound (4AB) or (4B), and a catalytic amount of N can be added, N-dimethylformamide, N-methylpyrrolidone, etc. are used as additives. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[production method 7]

Production method for compound (4-3g)

[chemical formula 27]

In the above formula, R ² , R ³ , A, E, G and n represent the same as defined above; X ⁴ represents a halogen atom such as chlorine atom, bromine atom or iodine atom, or a sulfonate such as methyl a leaving group for sulfonate, p-toluenesulfonate or triflate; and Pro ⁴ represents a known protecting group for carboxylic acids such as ethyl.

Compound (4CB) may be a commercially available product, or may be produced from a commercially available product by a known method. Alternatively, it can be produced by the method described in the production examples in any of the examples below or a similar method.

Compound (4CA) or (4D) may be a commercially available product, or may be produced from a commercially available product by a known method.

[Process 7-1]

In this procedure, compound (4CA) is reacted with a halogenating agent to give compound (4CB) or with a sulfonating agent to give compound (4CB). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, a nitrile solvent such as acetonitrile, a halogenated A hydrocarbon solvent such as methylene chloride, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, water, or a mixed solvent of these. In the halogenation reaction, an excess of a hydrohalic acid such as hydrochloric acid or hydrobromic acid may be used. In this case, an inorganic chloride such as zinc chloride or lithium bromide, a phase transfer catalyst or the like may be used. Alternatively, this reaction can be carried out by using a phosphorus halide compound such as phosphorus trichloride as a halogenating agent. In this case, N,N-dimethylformamide can be used as an iminium salt. Alternatively, a combination of an organophosphorus compound such as triphenylphosphine and a carbon tetrahalide can be used as the halogenating agent. Alternatively, a halogenating agent such as thionyl chloride may be used. In this case, a base such as pyridine can be used as an additive. The halogenating agent can be used in an amount of 1 to 10 equivalents. In the sulfonation reaction, a sulfonating agent such as p-toluenesulfonyl chloride can be used in an amount of 1 to 10 equivalents, and a base such as triethylamine or pyridine can be used as an additive in an amount of 1 to 10 equivalents. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Procedure 7-2]

In this process, compound (4CB) is reacted with compound (4D) to give compound (4-3g). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an amide solvent such as N,N-dimethyl methyl formamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, an organic base such as triethylamine or an inorganic base such as cesium carbonate can be used for condensation. Compound (4D) is used in an amount of 1 to 10 equivalents to compound (4-CB), and the base can be added in an amount of 0 to 10 equivalents. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Pro ⁴ can be deprotected by known deprotection methods for carboxylic acids.

[production method 8]

Production method for compound (4CB-1)

[chemical formula 28]

In the above formula, what A and n represent is the same as defined above; X ³ represents a halogen atom such as a chlorine atom or a bromine atom; X ⁵ represents a halogen atom such as a bromine atom or an iodine atom; and Pro ⁴ represents a Known protecting groups for carboxylic acids such as ethyl.

Compounds (4E) and (4F) may be commercially available products, or may be produced from commercially available products by known methods.

[Procedure 8-1]

In this process, compound (4E) is reacted with compound (4F) to give compound (4CB-1). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an amide solvent such as N,N-dimethyl methyl formamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, an organic base such as triethylamine or an inorganic base such as potassium carbonate can be used for condensation. Compound (4F) can be used in an amount of 1 to 10 equivalents to compound (4E), and the base can be added in an amount of 1 to 10 equivalents. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Pro ⁴ can also be deprotected by known deprotection methods for carboxylic acids.

[production method 9]

Production method for compound (4-3b), (4-5a), (4-5b), (4-5c), (4-5d), (4-5e) or (4-5f)

[Production method 9-1]

Production method for compound (4-3b)

[chemical formula 29]

In the above formula, R ² , R ³ , A and E represent the same as defined above; X ⁶ represents a halogen atom such as chlorine atom, bromine atom or iodine atom, or a sulfonate such as trifluoromethanesulfonic acid A leaving group for salts; and Pro ⁴ represents a known protecting group for carboxylic acids such as ethyl.

Compounds (4GA) and (4GB) may be commercially available products, or may be produced from commercially available products by known methods. Alternatively, Compound (4GB) can be produced by the method described in Production Examples in any of the Examples below or by a similar method.

[Process 9-1-1]

In this procedure, compound (4GA) is reacted with a halogenating agent to give compound (4GB) or with a sulfonating agent to give compound (4GB). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, a halogenated hydrocarbon solvent such as dichloromethane, An amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, a nitrile solvent such as acetonitrile, or a mixed solvent of these. In the halogenation reaction, a phosphorus halide such as phosphorus pentabromide or a halogenating agent such as triphenylphosphine dibromide can be used in an amount of 1 to 5 equivalents. In the sulfonation reaction, a sulfonating agent such as trifluoromethanesulfonic anhydride can be used in an amount of 1 to 5 equivalents, and a base such as triethylamine or pyridine can be used as an additive in an amount of 1 to 10 equivalents. The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 9-1-2]

In this procedure, compound (4GB) is reacted with compound (4D) to give compound (4-3b). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an amide solvent such as N,N-dimethyl methyl formamide or N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent of these. In this reaction, an organic base such as triethylamine or an inorganic base such as cesium carbonate can be used for condensation. Compound (4D) can be used in an amount of 1 to 10 equivalents to compound (4GB), and the base can be added in an amount of 0 to 10 equivalents. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Furthermore, in this reaction, a heavy metal such as copper may be added, and a palladium-containing organometallic catalyst and an organophosphorus ligand may also be added. Pro ⁴ can be deprotected by known deprotection methods for carboxylic acids.

[Production method 9-2]

Production method for compound (4-5a)

[chemical formula 30]

In the above formula, R ² , R ³ , A, E and n represent the same as defined above; Pro ¹ represents a known protecting group for nitrogen atom such as tert-butoxycarbonyl; and Pro ⁵ represents a known protecting group for carboxylic acids such as ethyl or benzyl.

Compounds (4H) and (4I) may be commercially available products, or may be produced from commercially available products by known methods.

[Process 9-2-1]

In this process, compound (4H) reacts with compound (4I) to give a compound (4-5a). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene, a Halogenated hydrocarbon solvent such as methylene chloride, an ester solvent such as ethyl acetate, or a mixed solvent of these. In this reaction, compound (4H) can be used in an amount of 0.5 to 2 equivalents to compound (4I). In this reaction, azodicarboxylates such as diisopropyl azodicarboxylate and triphenylphosphine can be used in an amount of 1 to 5 equivalents to compounds (4H) and (4I), respectively. The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Pro ⁵ can be deprotected by known deprotection methods for carboxylic acids.

[Production method 9-3]

Production method for compound (4-5b) or (4-5c)

[chemical formula 31]

In the above formula, R ² , R ³ , A and E represent the same as defined above; X ⁵ represents a halogen atom such as a bromine atom or an iodine atom; X ⁷ represents a halogen atom such as a bromine atom or an iodine atom, or a leaving group of a sulfonate such as methanesulfonate or triflate; M represents a leaving group of boronate or similar; Pro ¹ represents a known protection for the nitrogen atom group such as tert-butoxycarbonyl; and Pro ⁵ represents a known protecting group for carboxylic acids such as ethyl or benzyl, and the carboxylic acid may or may not be protected in this reaction.

Compounds (4J), (4K) and (4L) may be commercially available products, or may be produced from commercially available products by known methods.

[Process 9-3-1]

In this process, compound (4J) reacts with compound (4K) to give a compound (4-5b). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene, a An amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or a mixed solvent of these. In this reaction, compound (4K) can be used in an amount of 0.5 to 2 equivalents to compound (4J). In this reaction, a palladium complex containing an organophosphorus compound as a ligand can be used as a catalyst. The catalyst can be prepared within the reaction system. In this reaction, a zinc powder can be used in an amount of 0.5 to 2 equivalents to compound (4J). In addition, a copper halide, a bishalogenated alkyl compound, a halogenated organosilicon compound, or the like may be added as an additive. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Pro ⁵ can be deprotected by known deprotection methods for carboxylic acids.

[Process 9-3-2]

In this process, compound (4J) reacts with compound (4L) to give a compound (4-5c). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example an ether solvent such as 1,4-dioxane, an aromatic hydrocarbon A solvent such as toluene, an alcohol solvent such as ethanol, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or a mixed solvent of these. In this reaction, compound (4L) can be used in an amount of 0.5 to 2 equivalents to compound (4J). In this reaction, a palladium complex containing an organophosphorus compound as a ligand can be used as a catalyst. The catalyst can be prepared within the reaction system. In this reaction, a base such as sodium carbonate can be used in an amount of 1 to 10 equivalents to compound (4J). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 9-3-3]

In this process, compound (4-5c) is reduced and deprotected to give compound (4-5b). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an ester solvent such as ethyl acetate, an An alcohol solvent such as ethanol, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or a mixed solvent of these. In this reaction, a catalytic reduction catalyst such as palladium-carbon can be used in an amount of 0.001 to 1 equivalent to the compound (4-5c). In addition, the present reaction can be performed under a hydrogen atmosphere at a pressure ranging from normal pressure to 20 atm. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Pro ⁵ can be deprotected by known deprotection methods for carboxylic acids.

[Production method 9-4]

Production method for compound (4-5d) or (4-5e)

[chemical formula 32]

In the above formula, R ³ , A and E represent the same as defined above; X ⁸ represents a halogen atom such as a fluorine atom; Pro ¹ represents a known protecting group for a nitrogen atom such as tert-butoxy and Pro ⁴ represents a known protecting group for carboxylic acids such as ethyl, and the carboxylic acid may or may not be protected in this reaction.

Compound (4-5c) may be a commercially available product, or may be produced from a commercially available product by a known method. Alternatively, it can be produced by the method described in the production examples in any of the examples below or a similar method.

[Process 9-4-1]

In this process, compound (4-5c) is reacted to give compound (4-5d). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example an ether solvent such as tetrahydrofuran can be used. In this reaction, a borane complex such as borane-methylsulfide complex can be used in an amount of 1 to 2 equivalents to the compound (4-5c). The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Subsequently, hydroxyl groups are obtained by using an aqueous sodium hydroxide solution in an amount of 1 to 10 equivalents and a hydrogen peroxide solution in an amount of 1 to 10 equivalents. The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Process 9-4-2]

In this process, the hydroxyl group of compound (4-5d) is substituted with halogen to give compound (4-5e). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, a halogenated hydrocarbon solvent such as dichloromethane, an ether solvent such as tetrahydrofuran, An ester solvent such as ethyl acetate, an amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, or a mixed solvent of these. In this reaction, a halogenating agent such as [bis-(2-methoxyethyl)-amino]sulfur trifluoride can be used in an amount of 1 to 10 equivalents to the compound (4-5d). The reaction temperature is from 0°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Pro ⁴ can be deprotected by known deprotection methods for carboxylic acids.

[Production method 9-5]

Production method for compound (4-5f)

[chemical formula 33]

In the above formula, R ² , R ³ , A and E represent the same as defined above; X ⁷ represents a halogen atom such as a bromine atom or an iodine atom, or a sulfonate such as methanesulfonate or trifluoromethane A leaving group for sulfonate; Pro ¹ represents a known protecting group for nitrogen atoms such as tert-butoxycarbonyl; and Pro ⁴ represents a known protecting group for carboxylic acids such as ethyl , and the carboxylic acid may or may not be protected in this reaction.

Compounds (4-5b) and (4K) may be commercially available products, or may be produced from commercially available products by known methods. Alternatively, these compounds can be produced by the methods described in Production Examples in any of the Examples below or by similar methods.

[Process 9-5-1]

In this process, compound (4-5b) reacts with compound (4K) to give a compound (4-5f). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, an amide solvent such as N,N-dimethyl methyl formamide or N-methylpyrrolidone, or a mixed solvent of these. In this reaction, compound (4K) can be used in an amount of 0.5 to 2 equivalents to compound (4-5b). In addition, a base such as sodium hydride or potassium tert-butoxide can be used in an amount of 1 to 5 equivalents to the compound (4-5b). The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours. Pro ⁴ can be deprotected by known deprotection methods for carboxylic acids.

[Production method 10]

Production method for compound (4K)

[chemical formula 34]

In the above formula, R ² , R ³ and E represent the same as defined above; X ⁷ represents a halogen atom such as a bromine atom or an iodine atom, or a sulfonate such as methanesulfonate or trifluoromethanesulfonic acid a leaving group of the salt; and Pro ¹ represents a known protecting group for the nitrogen atom such as tert-butoxycarbonyl.

Compound (5K) may be a commercially available product, or may be produced from a commercially available product by a known method.

[process 10]

In this procedure, compound (5K) is reacted with a halogenating agent to give compound (4K) or with a sulfonating agent to give compound (4K). The solvent used in this reaction is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction, and for example, an ether solvent such as tetrahydrofuran, a halogenated hydrocarbon solvent such as dichloromethane, An amide solvent such as N,N-dimethylformamide or N-methylpyrrolidone, a nitrile solvent such as acetonitrile, or a mixed solvent of these. In the halogenation reaction, a phosphorus halide such as phosphorus pentabromide or a halogenating agent such as triphenylphosphine dibromide can be used in an amount of 1 to 5 equivalents. In the sulfonation reaction, a sulfonating agent such as methanesulfonyl chloride or trifluoromethanesulfonic anhydride can be used in an amount of 1 to 5 equivalents, and a base such as triethylamine or pyridine can be used in an amount of 1 to 10 equivalents as an additive. The reaction temperature is from -20°C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

example

The compound according to the present invention can be produced by the methods described in, for example, Production Examples and Examples below. However, these methods are merely examples, and thus the compounds according to the present invention are in no way limited to those produced by the specific examples described below.

In Production Examples and Examples, silica gel 60 (Kanto Chemicals Co.) or Presep silica gel (WAKO (Wako Corporation)) was used as purification silica gel for silica gel column chromatography unless otherwise specified. In addition, NH silica gel (Fuji Silysia Chemical LTD. (Fuji Silicon Chemical Co., Ltd.)) or Hi-Flash Column Amino (YAMAZENE company) was used as purification silica gel for NH silica gel column chromatography, and a TLC plate NH (20 cm × 20 cm , Fuji Silysia Chemical LTD. (Fuji Silicon Chemical Ltd.)) was used as a thin layer plate for NH silica gel TLC (thin layer chromatography).

A Varian Mercury 400, Varian Mercury Plus 400, Varian INOVA 500 or Avance 600 MHz spectrometer (Bruker) was used for the measurement of proton NMR spectra, and unless otherwise stated, the proton NMR spectra were measured at 400 MHz. Chemical shifts for proton NMR spectra are reported in delta (ppm) relative to tetramethylsilane and coupling constants are reported in Hertz (Hz). The abbreviations for the split form are as follows: s: singlet, d: doublet, t: triplet, q: quartet, quin: quintet; spt: septet; m: multiplet; and brs: broad peak.

A Waters Micromass ZQ 2000, Waters SQ Detector 2, or Thermo Fisher Scientific LCQ was used for mass spectrometric measurements. For the ionization method, an electrospray ionization (ESI) method was used for measurement.

In Production Examples and Examples, commercially available products were appropriately used as commercially available compounds. In the following description, the term "BOC" refers to tert-butoxycarbonyl and the term "T" refers to tertiary.

[instance 1]

6-Methoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-methyl Amide

[chemical formula 35]

The 4-(4-((4-((6-methoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine described in Examples 1-8 will be produced -2-yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (3.42g, 5.70mmol) was dissolved in dichloromethane (45mL) and trifluoroacetic acid (15ml) was added at 0°C . The mixture was stirred at room temperature for 60 minutes and then concentrated under vacuum, and then the residue was dissolved in dichloromethane-triethylamine, and the resultant was subjected to NH silica gel column chromatography (ethyl acetate:methanol =97:3-4:1) for purification. The target fraction was concentrated under vacuum, and then the precipitate was collected by filtration and washed with diethyl ether and ethyl acetate to obtain the title compound (2.61 g, 92%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.55-1.70 (2H, m), 1.78-1.88 (2H, m), 2.62-2.80 (3H, m), 3.06 (3H, d, J=4.8 Hz), 3.15-3.24(2H, m), 3.86(3H, s), 5.52-5.61(1H, m), 6.54(1H, d, J=3.3Hz), 6.60(1H, dd, J=5.7, 2.4Hz), 7.23(1H, d, J=3.7Hz), 7.28-7.35(3H, m), 7.80(2H, d, J=8.4Hz), 7.91(1H, d, J=2.2Hz), 8.03 (1H, s), 8.10 (1H, d, J=5.9Hz), 8.53 (1H, brs).

The starting material 4-(4-((4-((6-methoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine-2-yl) was synthesized by yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[Production Example 1-1]

(E)-2-(Benzyloxy)-1-methoxy-4-(2-nitrovinyl)benzene

[chemical formula 36]

Commercially available 3-benzyloxy-4-methoxybenzaldehyde (30 g, 124 mmol) was dissolved in acetic acid (100 mL), then ammonium acetate (10.8 g, 140 mmol) and nitric acid were added at room temperature under a nitrogen atmosphere. methyl methane (16.8 g, 310 mmol), and the mixture was heated and stirred at 130° C. for 2 hours and 20 minutes. The mixture was cooled to room temperature, and the precipitate was collected by filtration and washed with ethanol to obtain the title compound (28.5 g, 81%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.95 (3H, s), 5.18 (2H, s), 6.93 (1H, d, J=8.1Hz), 7.03 (1H, d, J=2.2Hz ), 7.17 (1H, dd, J = 8.4, 2.2Hz), 7.30-7.47 (6H, m), 7.91 (1H, d, J = 13.5Hz).

[Production example 1-2]

(E)-1-(Benzyloxy)-2-methoxy-4-nitro-5-(2-nitrovinyl)benzene

[chemical formula 37]

Under a nitrogen atmosphere at 25°C, 69% nitric acid (10 mL, 155 mmol) was added to (E)-2-(benzyloxy)-1-methoxy-4-(2 -nitrovinyl)benzene (10 g, 35.1 mmol) and acetic acid (70 mL) in a mixture, and the mixture was stirred at 40° C. for 3 hours. The reaction mixture was poured onto ice, and the precipitate was collected by filtration, and then washed with ethanol to obtain the title compound (10.5 g, 91%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.02 (3H, s), 5.28 (2H, s), 6.93 (1H, s), 7.22 (1H, d, J=13.5Hz), 7.35-7.48 (5H, m), 7.75 (1H, s), 8.58 (1H, d, J=13.2Hz).

[Production example 1-3]

6-methoxy-1H-indol-5-ol

[chemical formula 38]

(E)-1-(benzyloxy)-2-methoxy-4-nitro-5-(2-nitrovinyl)benzene (9.4 g, 28.5 mmol) described in Production Example 1-2 ) was suspended in methanol (300 mL), then 10% palladium-carbon (water content, 50%) (3.09 g) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hr. The catalyst was filtered off through celite and washed with methanol. The filtrate was concentrated under vacuum, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1-3:7). The target fractions were concentrated under vacuum to obtain the title compound (2.12 g, 46%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.92 (3H, s), 5.45 (1H, s), 6.39-6.44 (1H, m), 6.88 (1H, s), 7.08 (1H, t, J = 2.9 Hz), 7.14 (1H, s), 7.95 (1H, brs).

[Production example 1-4]

4-((6-methoxy-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 39]

Under a nitrogen atmosphere, 6-methoxy-1H-indol-5-ol (2.86 g, 17.6 mmol) described in Production Examples 1-3, N-(4 -Chloropyridin-2-yl)acetamide (8.98g, 52.7mmol), and potassium tert-butoxide (3.94g, 35.1mmol) were dissolved in dimethylsulfoxide (45mL) and the mixture was heated at 160°C Stir for 12.5 hours. The reaction liquid was cooled to room temperature, and water and ethyl acetate were added for segmentation. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed twice with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated in vacuo, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99 :1-9:1) for purification. The mixed fractions were concentrated under vacuum, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-9:1) Purified and then the target fractions were concentrated under vacuum to obtain a crude product (3.88g).

The crude product (3.88 g) was dissolved in methanol (75 mL), 28% sodium methoxide (14 mL, 68.6 mmol) was added at room temperature under a nitrogen atmosphere, and then the mixture was heated and stirred at 70° C. for 5.5 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added for segmentation. The aqueous layer was extracted once with ethyl acetate, and the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, the filtrate was concentrated in vacuo, and then the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:3-0:1-ethyl acetate:methanol=99 :1-19:1) for purification. The target fractions were concentrated under vacuum to obtain the title compound (1.97 g, 44%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.82 (3H, s), 4.29 (2H, brs), 5.89-5.92 (1H, m), 6.30 (1H, dd, J=5.9, 2.2Hz) , 6.49 (1H, ddd, J = 3.2, 2.2, 0.9Hz), 7.01 (1H, s), 7.17 (1H, dd, J = 3.1, 2.4Hz), 7.33 (1H, s), 7.89 (1H, d , J=6.0Hz), 8.19 (1H, brs).

[Production example 1-5]

N-(4-chloropyridin-2-yl)acetamide

[chemical formula 40]

Commercially available 2-amino-4-chloropyridine (50 g, 389 mmol) was dissolved in acetic anhydride (500 mL), triethylamine (271 mL, 1.94 mol) was added at 20° C., and the mixture was heated at 60° C. Stir for 12 hours. The mixture was cooled to room temperature, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1), and then the target fraction was concentrated in vacuo to obtain the title compound (66 g, 99%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.21 (3H, s), 7.05 (1H, dd, J=5.4, 1.9Hz), 8.15 (1H, d, J=5.4Hz), 8.30 (2H , brs).

[Production example 1-6]

5-((2-aminopyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole-1-carboxamide

[chemical formula 41]

4-((6-methoxy-1H-indol-5-yl)oxy)pyridin-2-amine (1.7 g, 6.66 mmol) described in Production Example 1-4 was dissolved in N,N- To dimethylformamide (25 mL) was added 50%-72% oily sodium hydride (424 mg) at 0°C under nitrogen atmosphere, and then the mixture was stirred at room temperature for 45 minutes. The mixture was cooled to 0°C again, methyl phenylcarbamate (1.64 g, 10.8 mmol) described in Production Example 1-7 was added, and the resultant was stirred at room temperature for 3 hours. To the reaction mixture were added saturated aqueous ammonium chloride, water and ethyl acetate for fractionation. The aqueous layer was extracted once with ethyl acetate, and the combined organic layers were washed with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under vacuum, and then the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:3-0:1-ethyl acetate:methanol= 99:1-19:1) for purification. The target fraction was concentrated under vacuum, and then the precipitate was collected by filtration and washed with ethyl acetate to obtain the title compound (1.37 g, 66%). The mixed fractions were concentrated under vacuum, and purified by NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-19:1). The target fraction was concentrated under vacuum, and then the precipitate was collected by filtration and washed twice with ethyl acetate to obtain the title compound (387 mg, 19%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.07 (3H, d, J=4.6Hz), 3.86 (3H, s), 4.31 (2H, brs), 5.44-5.56 (1H, m), 5.89 (1H, d, J = 2.2Hz), 6.27 (1H, dd, J = 5.9, 2.2Hz), 6.55 (1H, d, J = 3.7Hz), 7.23 (1H, d, J = 3.7Hz), 7.25 -7.28 (1H, m), 7.89 (1H, d, J=5.9Hz), 8.01 (1H, brs).

The reagent, methyl phenylcarbamate, was synthesized by the following method.

[Production example 1-7]

Methyl phenylcarbamate

[chemical formula 42]

A mixture of commercially available methylamine hydrochloride (50 g, 0.74 mol), pyridine (124 mL, 1.53 mol), and N,N-dimethylformamide (500 mL) was stirred at 5° C. Commercially available phenyl chloroformate (94 mL, 0.75 mol) was added dropwise over 2 hours. After the dropwise addition was complete, the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was added to ice water (2 L), and extracted twice with ethyl acetate (1.5 L). The organic layer was washed with water (1 L) and a saturated saline solution (300 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. To the concentrated residue were added n-heptane and ethyl acetate, and the precipitate was collected by filtration and washed with n-heptane and methyl tert-butyl ether to obtain the title compound (74.2 g, 66%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.90 (3H, d, J=4.9Hz), 4.95 (1H, brs), 7.08-7.16 (2H, m), 7.16-7.24 (1H, m) , 7.31-7.41 (2H, m)

[Production example 1-8]

4-(4-((4-((6-methoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)benzene Base) tert-butyl piperidine-1-carboxylate

[chemical formula 43]

Benzotriazole (2.32 g, 19.5 mmol) was dissolved in dichloromethane (100 mL), thionyl chloride (1.4 mL, 19.2 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (5.4 g, 17.7 mmol) described in Production Example 1-12 at room temperature, and The mixture was stirred for 25 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate, and then the anhydrous sodium sulfate was washed with dichloromethane, and then the filtrate was added to the The 5-((2-aminopyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole-1-carboxamide (2.5g, 8.01mmol), triethyl Amine (11 mL, 9.38 mmol), and 4-dimethylaminopyridine (101 mg, 0.827 mmol) in a mixture in tetrahydrofuran (80 mL). The resultant was stirred at room temperature for 5 hours, and then the reaction mixture was concentrated under vacuum. Water and ethyl acetate were added to the residue for fractionation, and the organic layer was washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was dissolved in tetrahydrofuran, an excess of 9.8M methylamine in methanol was added at room temperature, and the mixture was stirred for 50 minutes. The reaction mixture was concentrated under vacuum, the residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:3-0:1 ) for purification. The target fraction was concentrated under vacuum, and the precipitate was collected by filtration and washed with diethyl ether and ethyl acetate to obtain the title compound (3.15 g, 66%). The filtrate was combined with the mixed fractions, and the resultant was concentrated in vacuo and dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1: 3-0:1) for purification. The target fraction was concentrated under vacuum, and the precipitate was collected by filtration and washed with diethyl ether and ethyl acetate to obtain the title compound (264 mg, 5.5%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.48 (9H, s), 1.55-1.69 (2H, m), 1.77-1.87 (2H, m), 2.64-2.89 (3H, m), 3.02- 3.07(3H, m), 3.86(3H, s), 4.26(2H, brs), 5.62(1H, brs), 6.50-6.55(1H, m), 6.61(1H, dd, J=5.9, 2.2Hz) , 7.22(1H, d, J=3.7Hz), 7.27-7.33(3H, m), 7.80(2H, d, J=8.4Hz), 7.90(1H, d, J=2.2Hz), 8.04(1H, s), 8.09 (1H, d, J = 5.9 Hz), 8.54 (1H, brs).

4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid was synthesized by the following method.

[Production example 1-9]

1-(4-Phenylpiperidin-1-yl)ethanone

[chemical formula 44]

A mixture of commercially available 4-phenylpiperidine (10 g, 62 mmol), pyridine (5.7 mL, 70.5 mmol), and tetrahydrofuran (80 mL) was stirred at 0 °C and acetyl chloride was added dropwise over 10 minutes (5 mL, 70.3 mmol) and tetrahydrofuran (20 mL). The mixture was stirred at 25°C under nitrogen atmosphere for 14 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction liquid for separation. The aqueous layer was extracted with ethyl acetate (100 mL), then the organic layers were combined, and the resultant was washed with a saturated aqueous sodium bicarbonate solution (100 mL), water (100 mL), and then washed with a saturated saline solution (50 mL) washing. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated to obtain the title compound (12.3 g, 98%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.52-1.78 (2H, m), 1.81-1.99 (2H, m), 2.14 (3H, s), 2.63 (1H, td, J=12.9, 2.7 Hz), 2.74(1H, tt, J=12.1, 3.7Hz), 3.17(1H, td, J=13.2, 2.6Hz), 3.84-4.02(1H, m), 4.69-4.89(1H, m), 7.08 -7.43 (5H, m).

[Production example 1-10]

4-(1-Acetylpiperidin-4-yl)benzoic acid

[chemical formula 45]

A mixture of aluminum(III) chloride (26 g, 195 mmol) and dichloromethane (200 mL) was stirred at 0 °C and oxalyl chloride (20 mL, 228 mmol) was added dropwise over 10 minutes. Then a mixture of 1-(4-phenylpiperidin-1-yl)ethanone (12.3 g, 60.5 mmol) and dichloromethane (50 mL) described in Production Example 1-9 was added dropwise over 30 minutes . The mixture was stirred at 25°C under nitrogen atmosphere for 14 hours. The reaction liquid was poured onto ice, and ethyl acetate (1 L) and water (1 L) were added for separation. The aqueous layer was extracted twice with ethyl acetate (1 L), and then the organic layer was washed twice with water (1 L), and then washed with a saturated saline solution (500 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. Ethyl acetate was added to the concentrated residue, and the product was collected by filtration and washed with ethyl acetate to obtain the title compound (9.09 g, 61%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.49-1.82 (2H, m), 1.92 (2H, t, J = 13.2Hz), 2.15 (3H, s), 2.65 (1H, t, J = 11.7Hz), 2.75-2.94(1H, m), 3.08-3.30(1H, m), 3.97(1H, d, J=13.2Hz), 4.82(1H, d, J=12.8Hz), 7.30(2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.1 Hz).

[Production example 1-11]

4-(Piperidin-4-yl)benzoic acid hydrochloride

[chemical formula 46]

A solution of 4-(1-acetylpiperidin-4-yl)benzoic acid (4.50 g, 18.2 mmol) and 5M hydrochloric acid (50 mL, 250 mmol) described in Production Example 1-10 was dissolved under a nitrogen atmosphere at 140° C. The mixture was stirred for 18 hours. The mixture was cooled to room temperature, and then the product was collected by filtration and washed with water to obtain the title compound (3.77 g, 86%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.60-2.15 (4H, m), 2.76-3.16 (3H, m), 3.27-3.45 (2H, m), 7.36 (2H, d, J = 8.1 Hz), 7.92 (2H, d.

[Production example 1-12]

4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid

[chemical formula 47]

4-(Piperidin-4-yl)benzoic acid hydrochloride (2.00 g, 8.27 mmol) and 1 M sodium hydroxide solution (25 mL, 25 mmol) described in Production Examples 1-11 were mixed at 25° C., and A mixture of acetone (50 mL) was stirred and a solution of di-tert-butyl dicarbonate (1.9 g, 8.71 mmol) in acetone (25 mL) was added dropwise over 10 minutes. The mixture was stirred at 25°C under nitrogen atmosphere for 18 hours. 1M hydrochloric acid (17 mL) was added while cooling at 0 °C. The mixture was extracted twice with ethyl acetate (100 mL). The organic layer was washed with saturated saline solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under vacuum. To the concentrated residue were added n-heptane and methyl tert-butyl ether, and the product was collected by filtration and washed with n-heptane to obtain the title compound (2.30 g, 91%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.49 (9H, s), 1.57-1.76 (2H, m), 1.84 (2H, d, J=13.5Hz), 2.62-2.97 (3H, m) , 4.27 (2H, brs), 7.28-7.36 (2H, m), 7.98-8.10 (2H, m).

[Example 2]

5-((2-(4-(1-ethylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole -1-formamide;

[chemical formula 48]

To 6-methoxy-N-methyl-5-((2- A mixture of (4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (3.03 g, 6.06 mmol) and tetrahydrofuran (80 mL) , and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added ethyl acetate, saturated aqueous sodium bicarbonate solution and water for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, the obtained residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate:methanol=99: 1-9:1) for purification. The target fractions were concentrated under vacuum, and the residue was collected by filtration and washed with n-heptane and diethyl ether to obtain the title compound (2.61 g, 82%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.12 (3H, t, J=7.1Hz), 1.77-1.90 (4H, m), 1.98-2.07 (2H, m), 2.45 (2H, q, J=7.1Hz), 2.52-2.62(1H, m), 3.05-3.12(5H, m), 3.83(3H, s), 5.50-5.58(1H, m), 6.55(1H, d, J=3.7Hz ), 6.60 (1H, dd, J = 5.9, 2.4Hz), 7.23 (1H, d, J = 3.7Hz), 7.30-7.35 (3H, m), 7.79 (2H, d, J = 8.2Hz), 7.91 (1H, d, J = 2.4Hz), 8.03 (1H, s), 8.10 (1H, d, J = 5.7Hz), 8.50 (1H, brs).

[Example 3]

5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl -1H-Indole-1-carboxamide

[chemical formula 49]

Under a nitrogen atmosphere, commercially available 2-glycolaldehyde (110 mg, 1.83 mmol), sodium triacetoxyborohydride (382 mg, 1.80 mmol) and acetic acid (103 μL, 1.80 mmol) were added to the mixture described in Example 1. 6-methoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1- formamide (300 mg, 0.601 mmol) and tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, the obtained residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (ethyl acetate:methanol=99:1-4:1). The target fraction and the mixed fraction were concentrated in vacuo, and the residue of the mixed fraction was purified by NH silica gel column chromatography (ethyl acetate:methanol=97:3-19:1-23:2). The combined target fractions were concentrated under vacuum, and the precipitate was collected by filtration and washed with diethyl ether and ethyl acetate to obtain the title compound (209 mg, 64%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.70-1.90 (4H, m), 2.14-2.25 (2H, m), 2.53-2.65 (3H, m), 2.97-3.09 (2H, m), 3.06(3H, d, J=4.4Hz), 3.63(2H, t, J=5.3Hz), 3.86(3H, s), 5.51-5.60(1H, m), 6.54(1H, d, J=3.7Hz ), 6.61 (1H, dd, J=5.7, 2.4Hz), 7.23 (1H, d, J=3.7Hz), 7.29-7.35 (3H, m), 7.80 (2H, d, J=8.4Hz), 7.91 (1H,d,J=2.6Hz), 8.04(1H,s), 8.10(1H,d,J=5.9Hz), 8.51(1H,brs).

[Example 4]

(S)-5-((2-(4-(1-(2-hydroxypropyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy- N-Methyl-1H-indole-1-carboxamide

[chemical formula 50]

Commercially available (S)-(-)-propylene oxide (233 mg, 4.00 mmol) was added to 6-methoxy-N-methyl-5-((2-(4-( piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (400mg, 0.801mmol) in a mixture of ethanol (10mL), and the The mixture was heated and stirred at 60° C. for 1 hour with a sealed tube. The mixture was cooled to room temperature, and then tetrahydrofuran (5.0 mL) was added, and the mixture was heated and stirred at 70° C. for 2 hr. The reaction mixture was concentrated in vacuo, the resulting residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate ester:methanol=99:1-19:1) for purification. The target fraction was concentrated under vacuum, and the precipitate was collected by filtration and washed with diethyl ether and ethyl acetate to obtain the title compound (347 mg, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.14 (3H, d, J=6.2Hz), 1.66-1.89 (4H, m), 1.98-2.09 (1H, m), 2.21-2.45 (3H, m), 2.52-2.64(1H, m), 2.88-2.96(1H, m), 3.06(3H, d, J=4.8Hz), 3.10-3.17(1H, m), 3.57(1H, brs), 3.80 -3.92(1H, m), 3.86(3H, s), 5.52-5.59(1H, m), 6.54(1H, d, J=3.7Hz), 6.60(1H, dd, J=5.9, 2.6Hz), 7.23(1H, d, J=3.7Hz), 7.29-7.35(3H, m), 7.78-7.83(2H, m), 7.91(1H, d, J=2.6Hz), 8.03(1H, s), 8.10 (1H, d, J = 5.9 Hz), 8.53 (1H, brs).

[Example 5]

5-((2-(4-(1-(3-fluoropropyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl -1H-Indole-1-carboxamide

[chemical formula 51]

Triethylamine (11.8 μL, 0.085 mmol) and 3-fluoropropyl 4-methylbenzenesulfonate (16.1 mg, 0.069 mmol) described in Production Example 5-1 were added to 6 -Methoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (14.1 mg, 0.028 mmol) and N,N-dimethylformamide (0.5 mL), and the mixture was heated and stirred at 50° C. for 1 hour and then at room temperature for 13 hours. Triethylamine (11.8 μL, 0.085 mmol) and 3-fluoropropyl 4-methylbenzenesulfonate (16.1 mg, 0.069 mmol) were added to the reaction mixture, and the mixture was heated and stirred at 50° C. 3 hours. The resultant was cooled to room temperature, and then water and ethyl acetate were added for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, the obtained residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1-ethyl acetate:methanol=99: 1-19:1-9:1) for purification. The target fractions were concentrated under vacuum, and the precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (10.2 mg, 65%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.72-2.00 (6H, m), 2.02-2.13 (2H, m), 2.47-2.62 (3H, m), 3.01-3.09 (2H, m), 3.06(3H, d, J=4.8Hz), 3.86(3H, s), 4.47(1H, t, J=6.0Hz), 4.59(1H, t, J=6.0Hz), 5.48-5.58(1H, m ), 6.55 (1H, d, J = 3.7Hz), 6.60 (1H, dd, J = 5.7, 2.4Hz), 7.23 (1H, d, J = 3.7Hz), 7.30-7.34 (3H, m), 7.77 -7.82 (2H, m), 7.91 (1H, d, J=2.6Hz), 8.03 (1H, s), 8.10 (1H, d, J=6.2Hz), 8.50 (1H, brs).

The reagent 3-fluoropropyl 4-methylbenzenesulfonate was synthesized by the following method.

[Production example 5-1]

3-fluoropropyl 4-methylbenzenesulfonate

[chemical formula 52]

Triethylamine (11 mL, 79.4 mmol), 4-dimethylaminopyridine (390 mg, 3.19 mmol), and p-toluenesulfonyl chloride (13.4 g, 70.4 mmol) were added to a commercially available solution at 0 °C under a nitrogen atmosphere. in a mixture of commercially available 3-fluoropropan-1-ol (5.0 g, 64 mmol) and tetrahydrofuran (120 mL), and the mixture was stirred at room temperature for 90 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with water and saturated saline solution, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, the resulting residue was dissolved in dichloromethane and n-heptane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=10:1-2:1) to obtain the title Compound (12.7 g, 85%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.97-2.15 (2H, m), 2.46 (3H, s), 4.16 (2H, t, J=6.2Hz), 4.49 (2H, dt, J= 46.8, 5.6 Hz), 7.36 (2H, dd, J = 8.4, 0.6 Hz), 7.75-7.85 (2H, m).

[Example 6]

5-((2-(4-(3-fluoropiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole- 1-formamide

[chemical formula 53]

3-Fluoro-4-(4-((4-((6-methoxy-1-(methylcarbamoyl)-1H-indol-5-yl) as described in Example 6-5 will be produced Oxy)pyridin-2-yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (29.1 mg, 0.047 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid was added at room temperature (0.8 mL, 10.4 mmol), and then the mixture was stirred for 30 minutes. The solvent was evaporated, the resulting residue was dissolved in dichloromethane (4 mL), and triethylamine was added to neutralize excess trifluoroacetic acid. The solvent was evaporated, and the resulting residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate:methanol=97 :3-19:1) to obtain the title compound (16.8 mg, 69%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 1.71-1.80 (2H, m), 1.89-1.97 (1H, m), 2.63-2.70 (1H, m), 2.70-2.76 (1H, m ), 2.79-2.89 (1H, m), 3.05 (3H, d, J = 4.9Hz), 3.09 (1H, d, J = 11.2Hz), 3.48 (1H, dt, J = 11.3, 4.1Hz), 3.87 (3H, s), 4.58 (1H, dtd, J = 50.0, 9.9, 4.6Hz), 5.58 (1H, q, J = 4.7Hz), 6.54 (1H, d, J = 3.4Hz), 6.61 (1H, dd, J = 5.6, 2.2Hz), 7.22 (1H, d, J = 3.9Hz), 7.32 (1H, s), 7.38 (2H, d, J = 8.3Hz), 7.84 (2H, d, J = 8.3 Hz), 7.91 (1H, d, J = 2.4 Hz), 8.04 (1H, s), 8.10 (1H, d, J = 5.9 Hz), 8.57 (1H, s).

The starting material 3-fluoro-4-(4-((4-((6-methoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)) was synthesized by pyridin-2-yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[Production example 6-1]

tert-butyl 4-(4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

[chemical formula 54]

Under a nitrogen atmosphere, toluene (20 mL), ethanol (6 mL), and water (2 mL) were added to commercially available 1-N-BOC-4-(4,4,5,5-tetramethyl-[1 , 3,2] dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (1.00g, 3.23mmol), methyl 4-bromobenzoate (695mg, 3.23mmol), 2 - Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (266mg, 0.65mmol), palladium(II) acetate (73mg, 0.32mmol), and tripotassium phosphate (2.06g, 9.70mmol) , and the mixture was stirred at 90 °C for 5 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate and ethyl acetate were added for fractionation. The aqueous layer was extracted three times with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1-13:7) to obtain the title compound (0.99 g, 96%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 1.49 (9H, s), 2.55 (2H, brs), 3.65 (2H, t, J=5.9Hz), 3.92 (3H, s), 4.10 (2H, brs), 6.16 (1H, brs), 7.43 (2H, d, J = 8.3 Hz), 8.00 (2H, d, J = 8.8 Hz).

[Production example 6-2]

tert-butyl 3-hydroxy-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[chemical formula 55]

tert-butyl 4-(4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (776 mg, 2.45 mmol) described in Production Example 6-1 was dissolved in tetrahydrofuran (10 mL), a solution of borane-methylsulfide complex (0.269 mL, 2.69 mmol) in tetrahydrofuran (10 mL) was added at room temperature over 3 minutes, and the mixture was stirred for 13 hours. The reaction liquid was cooled to 0 °C, and 1M sodium hydroxide solution (6.12 mL, 6.12 mmol) was added over one minute. 30% aqueous hydrogen peroxide (0.625 mL, 6.12 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture were successively added saturated aqueous sodium thiosulfate (20 mL), water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, and then the organic layers were combined, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:4) to obtain the title compound (518 mg, 63%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 1.49 (9H, s), 1.59 (1H, d, J=2.9Hz), 1.69-1.88 (2H, m), 2.57-2.71 (2H, m), 2.77(1H, brs), 3.67-3.82(1H, m), 3.91(3H, s), 4.22(1H, brs), 4.42(1H, brs), 7.34(2H, d, J=8.3Hz ), 8.02 (2H, d, J = 8.3 Hz).

[Production example 6-3]

tert-butyl 3-fluoro-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[chemical formula 56]

tert-butyl 3-hydroxy-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (518 mg, 1.54 mmol) described in Production Example 6-2 was dissolved in dichloromethane (15 mL) [Bis-(2-methoxyethyl)amino]sulfur trifluoride (0.313 mL, 1.70 mmol) was added over 3 min at -78 °C, and the mixture was stirred while warming to room temperature for 1 Hour. To the reaction mixture were successively added saturated aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, and then the organic layers were combined, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1-3:2) to obtain the title compound (402 mg, 77%). ¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 1.49 (9H, s), 1.64-1.81 (1H, m), 1.86-2.01 (1H, m), 2.72-2.94 (3H, m), 3.91 (3H, s), 4.19 (1H, brs), 4.44-4.66 (2H, m), 7.33 (2H, d, J = 8.3Hz), 8.02 (2H, d, J = 8.3Hz).

[Production example 6-4]

4-(1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)benzoic acid

[chemical formula 57]

tert-butyl 3-fluoro-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (402 mg, 1.19 mmol) described in Production Example 6-3 was dissolved in tetrahydrofuran (18 mL), methanol (6 mL), and water (4 mL), then 2M aqueous lithium hydroxide solution (4.17 mL, 8.34 mmol) was added at room temperature, and the mixture was then stirred for 3 hours. Tetrahydrofuran and methanol were evaporated under vacuum, and 1M hydrochloric acid was added to the residual solution for neutralization. The aqueous layer was extracted four times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:4) to obtain the title compound (347 mg, 90%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 1.50 (9H, s), 1.77 (1H, qd, J=13.0, 3.9Hz), 1.92 (1H, d, J=14.1Hz), 2.72 -2.95 (3H, m), 4.21 (1H, brs), 4.46-4.67 (2H, m), 7.37 (2H, d, J=8.3Hz), 8.09 (2H, d, J=8.3Hz).

[Production example 6-5]

3-fluoro-4-(4-((4-((6-methoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)amino Formyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[chemical formula 58]

Thionyl chloride (30 μL, 0.319 mmol) was added to a mixture of benzotriazole (49.3 mg, 0.414 mmol) and dichloromethane (4 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 minute. 4-(1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)benzoic acid (103 mg, 0.319 mmol) described in Production Example 6-4 was added, and the mixture was heated at room temperature Stir for 30 minutes. The reaction liquid was filtered through anhydrous sodium sulfate, and the anhydrous sodium sulfate was washed with dichloromethane (4 mL) to obtain a dichloromethane solution of the crude product.

A dichloromethane solution (4 mL, 0.16 mmol) of the above crude product was added to 5-((2-aminopyridin-4-yl)oxy)-6 as described in Production Example 1-6 at 0°C -Methoxy-N-methyl-1H-indole-1-carboxamide (25.0mg, 0.080mmol), triethylamine (56μL, 0.40mmol), 4-dimethylaminopyridine (1.0mg, 0.008mmol ) and dichloromethane (1 mL), the mixture was then stirred at 0° C. for 10 minutes and then at room temperature for 3 hours. 40% Aqueous methylamine solution (138 μL, 1.60 mmol) was added, and the mixture was further stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The aqueous layer was extracted three times with ethyl acetate, and then the organic layers were combined, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1) to obtain the title compound (29.1 mg, 59%).

¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (9H, s), 1.65-1.82 (1H, m), 1.91 (1H, brs), 2.69-2.93 (3H, m), 3.04 ( 3H, d, J = 4.9Hz), 3.86 (3H, s), 4.18 (1H, brs), 4.42-4.66 (2H, m), 5.65 (1H, q, J = 4.4Hz), 6.53 (1H, d , J=3.4Hz), 6.62(1H, dd, J=5.9, 2.4Hz), 7.23(1H, d, J=3.9Hz), 7.31(1H, s), 7.36(2H, d, J=8.3Hz ), 7.84 (2H, d, J = 8.3Hz), 7.91 (1H, d, J = 2.0Hz), 8.05 (1H, s), 8.09 (1H, d, J = 5.9Hz), 8.63 (1H, s ).

[Example 7]

5-((2-(4-(4-fluoropiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole- 1-formamide

[chemical formula 59]

Benzotriazole (33.2 mg, 0.278 mmol) was dissolved in dichloromethane (10 mL) under nitrogen atmosphere, then thionyl chloride (20 μL, 0.278 mmol) was added, and the mixture was stirred at 20° C. for 5 minutes. To the reaction mixture was added 4-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)benzoic acid (60 mg, 0.186 mmol) described in Production Example 7-4, and The mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered and dichloromethane was evaporated under vacuum until the amount became as small as about 5 ml. 5-((2-aminopyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole-1-carboxamide (25 mg , 0.08 mmol), triethylamine (55 μL, 0.40 mmol), and 4-dimethylaminopyridine (1.96 mg, 0.016 mmol) were successively added to the resulting reaction mixture, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2M methylamine tetrahydrofuran solution (120 μL, 0.24 mmol), then the mixture was stirred at room temperature for 1 hour, and then ethyl acetate and saturated aqueous sodium bicarbonate were added for segmentation. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum and the resulting residue was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added at 0° C., and the mixture was then stirred at room temperature for 1 hr. The solvent was evaporated under vacuum, forming an azeotropic mixture with the resulting residue with toluene, and the mixture was then dried under vacuum. The obtained residue was dissolved in a mixed solvent of dichloromethane and triethylamine, and the resultant was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-17:3). The target fractions were concentrated in vacuo to obtain the title compound (11.8 mg, 29%). ¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.73-2.01 (4H, m), 2.91-3.23 (7H, m), 3.86 (3H, s), 5.76-5.91 (1H, m), 6.44- 6.52(1H, m), 6.64(1H, dd, J=5.9, 2.2Hz), 7.22(1H, d, J=3.7Hz), 7.31(1H, s), 7.48(2H, d, J=8.4Hz ) 7.81-7.97 (3H, m), 8.02-8.14 (2H, m), 8.74 (1H, brs).

The starting material 4-(1-tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)benzoic acid was synthesized by the following method.

[Production Example 7-1]

1-Benzyl-4-(4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)piperidin-4-ol

[chemical formula 60]

Magnesium (3.10 g, 127 mmol), iodine (135 mg, 0.531 mmol), and 2-(4-bromophenyl)-4,5-dihydro-4,4-dimethyloxazole (27 g, 106 mmol) were added into tetrahydrofuran (120 mL), and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, then 1-benzyl-4-piperidone (21.7 mL, 117 mmol) was added, and the mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous ammonium chloride solution and ethyl acetate were added for fractionation. The aqueous layer was extracted with ethyl acetate, and then the organic layers were combined and washed successively with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under vacuum, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1-1:1). The target fractions were concentrated under vacuum to obtain the title compound (13.4 g, 35%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.37 (6H, s), 1.67-1.76 (2H, m), 2.16 (2H, td, J = 13.1, 4.5Hz), 2.47 (2H, td, J=12.0, 2.5Hz), 2.79(2H, d, J=11.4Hz), 3.58(2H, s), 4.09(2H, s), 7.23-7.40(5H, m), 7.55(2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.6 Hz).

[Production Example 7-2]

4-(1-Benzyl-4-hydroxypiperidin-4-yl) ethyl benzoate

[chemical formula 61]

1-benzyl-4-(4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)piperidine-4 described in Production Example 7-1 - Alcohol (13.4 g, 36.8 mmol) was dissolved in ethanol (300 mL), then sulfuric acid was added, and the mixture was stirred at 90° C. for 12 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under vacuum. The obtained residue was dissolved in dichloromethane, the resultant was washed with a saturated aqueous sodium bicarbonate solution, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum, and the resulting residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1). The target fractions were concentrated in vacuo to obtain the title compound (7.23 g, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.39 (3H, t, J=7.1Hz), 1.59-1.85 (2H, m), 2.17 (2H, td, J=13.1, 4.5Hz), 2.47 (2H, td, J=12.0, 2.5Hz), 2.72-2.93(2H, m), 3.59(2H, s), 4.37(2H, q, J=7.0Hz), 7.14-7.44(5H, m), 7.59 (2H, d, J = 8.4 Hz), 8.02 (2H, d, J = 8.4 Hz).

[Production example 7-3]

tert-Butyl 4-(4-(ethoxycarbonyl)phenyl)-4-fluoropiperidine-1-carboxylate

[chemical formula 62]

Ethyl 4-(1-benzyl-4-hydroxypiperidin-4-yl)benzoate (6.23 g, 18.4 mmol) described in Production Example 7-2 was dissolved in dichloromethane (200 mL) under nitrogen atmosphere ), then diethylaminosulfur trifluoride (2.89 mL, 22.0 mmol) was added at -78°C, and the mixture was stirred at room temperature for 3 hours. Dichloromethane was added to the reaction mixture, and the mixture was washed with water, and then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under vacuum to obtain a crude product A (6.13 g).

The crude product A (6.13 g) was dissolved in dichloromethane (100 mL) under nitrogen atmosphere, then chloroethyl 1-chloroformate (2.13 mL, 19.8 mmol) was added, and the mixture was stirred at 20 °C for 2 hours . The reaction mixture was concentrated under vacuum, then the resulting residue was dissolved in methanol (100 mL), and the resultant was heated at reflux for 30 minutes. The reaction mixture was concentrated under vacuum, then diethyl ether was added to the resulting residue, the precipitate was collected by filtration, and the resultant was then washed with diethyl ether to obtain a crude product B (4.72 g).

Crude product B (4.72 g) was dissolved in dichloromethane (50 mL), then triethylamine (5.24 mL, 37.6 mmol) and di-tert-butyl dicarbonate (4.92 g, 22.5 mmol) were added, and the mixture was Stir at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture for fractionation. The aqueous layer was extracted again with ethyl acetate, and then the organic layers were combined and washed with water, and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under vacuum, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1). The title fractions were concentrated under vacuum to obtain the title compound (3.74 g, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.24-1.34 (1H, m), 1.40 (3H, t, J=7.1Hz), 1.50 (9H, s), 1.86-2.14 (2H, m) , 2.54(1H, brs), 3.18(1H, brs), 3.65(1H, t, J=5.7Hz), 4.00-4.26(2H, m), 4.38(2H, qd, J=7.1, 3.1Hz), 7.43 (2H, dd, J = 8.6, 1.3 Hz), 8.03 (2H, dd, J = 18.1, 8.6 Hz).

[Production example 7-4]

4-(1-tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)benzoic acid

[chemical formula 63]

tert-butyl 4-(4-(ethoxycarbonyl)phenyl)-4-fluoropiperidine-1-carboxylate (3.74 g, 10.6 mmol) described in Production Example 7-3 was dissolved in tetrahydrofuran (10 mL) and To a mixed solvent of methanol (5 mL), 1M sodium hydroxide solution (42.6 mL) was then added, and the mixture was stirred at 50° C. for 4 hr. 1M hydrochloric acid was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and then the resultant was dried by flow-through drying to obtain the title compound (1.33 g, 39%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.43 (9H, s), 1.83-2.15 (4H, m), 3.06 (2H, brs), 3.99 (2H, d, J=10.3Hz) , 7.50 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz).

[Example 8]

6-methoxy-N-methyl-5-((2-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzamide)pyridin-4-yl)oxy )-1H-indole-1-carboxamide

[chemical formula 64]

To 4-(4-(pyrrolidine- 1-yl)piperidin-1-yl)benzoic acid (44 mg, 0.16 mmol) in dichloromethane (2 mL). The reaction liquid mixture was stirred at room temperature for 1 hour. The reaction liquid mixture was concentrated, and to a solution of the residue in dichloromethane (2 mL) were successively added triethylamine (112 μL, 0.80 mmol), 5- ((2-aminopyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole-1-carboxamide (50mg, 0.16mmol), and 4-dimethylaminopyridine (3.91 mg, 0.032 mmol). The reaction liquid mixture was stirred at room temperature. To the reaction liquid, saturated aqueous sodium bicarbonate solution was added, and then ethyl acetate was added for dilution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1) to obtain the title compound (3.6 mg, 4.0%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.18-1.38 (2H, m), 1.84 (4H, brs), 1.95-2.11 (2H, m), 2.24-2.38 (1H, m), 2.70 ( 4H, brs), 2.82-2.96 (2H, m), 3.06 (3H, d, J=4.8Hz), 3.80-3.91 (5H, m), 5.52-5.68 (1H, m), 6.54 (1H, d, J=3.3Hz), 6.61(1H, dd, J=5.9, 2.2Hz), 6.89(2H, d, J=8.8Hz), 7.23(1H, d, J=3.7Hz), 7.32(1H, s) , 7.75 (2H, d, J = 8.8Hz), 7.90 (1H, d, J = 2.2Hz), 8.02 (1H, s), 8.09 (1H, d, J = 5.9Hz), 8.56 (1H, brs) .

The starting material 4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzoic acid was synthesized by the following method.

[Production example 8-1]

4-(4-(Pyrrolidin-1-yl)piperidin-1-yl)methyl benzoate

[chemical formula 65]

Commercially available methyl 4-fluorobenzoate (1.5 g, 9.73 mmol) was added to commercially available 4-(1-pyrrolidinyl)piperidine (3.0 g, 19.5 mmol) in dimethyl sulfoxide (15 mL), and then the mixture was stirred at 150° C. for 4 hours under a nitrogen atmosphere and under microwave irradiation. The reaction liquid was allowed to stand to cool to room temperature, and then diluted with water and ethyl acetate. The organic layer was washed with water, and then dried by a conventional method. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (2.06 g, 73%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.54-1.70 (2H, m), 1.74-1.88 (4H, m), 1.93-2.06 (2H, m), 2.12-2.26 (1H, m), 2.53-2.65 (4H, m), 2.90 (2H, td, J=12.4, 2.6Hz), 3.74-3.97 (5H, m), 6.86 (2H, d, J=9.2Hz), 7.89 (2H, d, J = 9.2 Hz).

[Production Example 8-2]

4-(4-(Pyrrolidin-1-yl)piperidin-1-yl)benzoic acid

[chemical formula 66]

5M sodium hydroxide solution (15 mL, 75.0 mmol) was added to methyl 4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzoate (2.06 g , 7.14 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL). The reaction liquid was stirred at 50°C for 4 hours. The reaction liquid was cooled to 0°C, and then 5M hydrochloric acid was added dropwise until the pH reached 1. The liquid mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was isolated by filtration and the filtrate was then concentrated under vacuum to obtain the title compound (1.61 g, 82%).

ESI-MS (m/z): 297 [M+H] ⁺ .

[Example 9]

5-((2-(4-((4-hydroxypiperidin-1-yl)methyl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl-1H -Indole-1-carboxamide

[chemical formula 67]

Triethylamine (1.6 mL, 11.5 mmol) and commercially available 4-(chloromethyl)benzoyl chloride (1.37 g, 7.25 mmol) were added to Production Example 1-6 at 0° C. under nitrogen atmosphere The 5-((2-aminopyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole-1-carboxamide (905mg, 2.90mmol) and tetrahydrofuran (28mL ) in a mixture. The mixture was stirred at room temperature for 100 minutes, then triethylamine (1.6 mL, 11.5 mmol) and 4-(chloromethyl)benzoyl chloride (0.90 g, 4.76 mmol) were added to the reaction mixture at 0 °C , and the resultant was then stirred at room temperature for 1.5 hours. To the reaction mixture were added water, tetrahydrofuran, and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The resultant was filtered with NH-silica gel (ethyl acetate) and then concentrated under vacuum to obtain a crude product.

The crude product was dissolved in N,N-dimethylformamide (15 mL), commercially available 4-hydroxypiperidine (1.48 g, 14.6 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred 16 hours. To the reaction mixture were added water and ethyl acetate for fractionation, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated saline solution, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, the obtained residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-9:1-17:3-4:1) . The target product was collected by filtration and washed with ethyl acetate to obtain the title compound (1.30 g, 84%). ¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.32-1.44 (2H, m), 1.64-1.74 (2H, m), 1.97-2.09 (2H, m), 2.59-2.69 (2H, m ), 2.86 (3H, d, J = 4.2Hz), 3.39-3.50 (3H, m), 3.76 (3H, s), 4.54 (1H, d, J = 4.2Hz), 6.63 (1H, d, J = 3.7Hz), 6.65(1H, dd, J=5.7, 2.2Hz), 7.37(2H, d, J=8.1Hz), 7.44(1H, s), 7.66(1H, d, J=2.4Hz), 7.78 (1H, d, J = 3.7Hz), 7.92 (2H, d, J = 8.2Hz), 8.10 (1H, s), 8.15-8.22 (2H, m), 10.68 (1H, s).

[Example 10]

5-((2-(4-(((3S,4S)-3-hydroxyl-4-methoxypyrrolidin-1-yl)methyl)benzamide)pyridin-4-yl)oxy)- 6-Methoxy-N-methyl-1H-indole-1-carboxamide

[chemical formula 68]

The crude product described in Example 9 (20.2 mg, 0.033 mmol) was dissolved in N,N-dimethylformamide (0.5 mL) and (3S,4S)-4- Methoxypyrrolidin-3-ol (55.9 mg, 0.477 mmol) (described in EP1375465) and the mixture was then stirred for 200 minutes. To the reaction mixture were added water and ethyl acetate for fractionation, and the organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was evaporated, and the resulting residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (ethyl acetate:methanol=1:0-19:1-9:1 ) for purification. The residue was washed with diethyl ether to obtain the title compound (13.8 mg, 77%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.32 (1H, dd, J=10.1, 4.2Hz), 2.61-2.68 (1H, m), 2.70-2.77 (1H, m), 3.03-3.16 ( 4H, m), 3.36 (3H, s), 3.62-3.76 (4H, m), 3.87 (3H, s), 4.12-4.19 (1H, m), 5.42-5.51 (1H, m), 6.56 (1H, d, J = 3.7Hz), 6.59-6.62 (1H, m), 7.23 (1H, d, J = 3.7Hz), 7.32 (1H, s), 7.42 (2H, d, J = 8.4Hz), 7.81 ( 2H,d,J=8.1Hz), 7.91(1H,d,J=2.2Hz), 8.03(1H,s), 8.11(1H,d,J=5.9Hz), 8.48(1H,brs).

[Example 11]

5-((2-(4-(2-(4-ethylpiperazin-1-yl)ethyl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl Amyl-1H-indole-1-carboxamide

[chemical formula 69]

Thionyl chloride (0.116 mL, 1.60 mmol) was added to commercially available 4-(2-chloroethyl)benzoic acid (88 mg, 0.479 mmol) and 1,2-dichloroethane at room temperature under nitrogen atmosphere methane (1.0 mL), and the mixture was heated at reflux at 90° C. for 1.5 hours. The mixture was cooled to room temperature, then the solvent was evaporated, and the resultant was dissolved in tetrahydrofuran (1.0 mL), and thus an acid chloride solution was prepared. Triethylamine (0.443 mL, 3.20 mmol) was added to 5-((2-aminopyridin-4-yl)oxy)-6-methanol as described in Production Examples 1-6 at room temperature under nitrogen atmosphere Oxy-N-methyl-1H-indole-1-carboxamide (49.9 mg, 0.160 mmol) and a mixture of N, N-dimethylformamide (0.5 mL), and the mixture was cooled to 0°C. The previously prepared tetrahydrofuran solution of the acid chloride was added at the same temperature, and the mixture was stirred at room temperature for 2.5 hours. Water and ethyl acetate were added to the reaction mixture for segmentation, and then the organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was dissolved in dichloromethane, the resultant was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=3:1-0:1), and then the target fraction Concentrate under vacuum to obtain a crude product (48.9 mg).

This crude product (48.9 mg) was dissolved in N,N-dimethylformamide (0.25 mL), then commercially available N-ethylpiperazine (129 μL, 1.02 mmol) was added at room temperature under nitrogen atmosphere and N,N-diisopropylethylamine (26.6 μL, 0.153 mmol), and the mixture was heated and stirred at 60° C. for 16 hours. The mixture was cooled to room temperature, then water and ethyl acetate were added to the reaction mixture for segmentation, and then the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99 :1-19:1) for purification. The mixed fractions were concentrated in vacuo, and the residue was purified by NH silica gel TLC (ethyl acetate) to obtain the title compound (7.03 mg, 16%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.10 (3H, t, J=7.3Hz), 2.44 (2H, q, J=7.0Hz), 2.35-2.70 (10H, m), 2.81-2.90 (2H, m), 3.07 (3H, d, J = 4.8Hz), 3.86 (3H, s), 5.43-5.51 (1H, m), 6.56 (1H, d, J = 3.7Hz), 6.60 (1H, dd, J = 5.9, 2.6Hz), 7.23 (1H, d, J = 3.7Hz), 7.28-7.33 (3H, m), 7.78 (2H, d, J = 8.4Hz), 7.91 (1H, d, J = 2.2 Hz), 8.03 (1H, s), 8.10 (1H, d, J = 5.9 Hz), 8.46 (1H, brs).

[Example 12]

5-((2-(4-(2-(4-hydroxypiperidin-1-yl)ethoxy)benzamide)pyridin-4-yl)oxy)-6-methoxy-N-methyl Amyl-1H-indole-1-carboxamide

[chemical formula 70]

Under a nitrogen atmosphere at room temperature, oxalyl chloride (44 μL, 0.513 mmol) and a catalytic amount of N,N-dimethylformamide were added to 4-(2-chloroethoxyl as described in Production Example 12-1 ) benzoic acid (51.2 mg, 0.255 mmol) and dichloromethane (2.0 mL), and the mixture was stirred for 45 minutes. To the reaction mixture was added oxalyl chloride (44 μL, 0.513 mmol) at room temperature, and the mixture was stirred for 30 minutes. The solvent was evaporated, and the resultant was dissolved in tetrahydrofuran (0.5 mL), and thus an acid chloride solution was prepared. At room temperature under a nitrogen atmosphere, triethylamine (89 μL, 0.64 mmol) was added to 5-((2-aminopyridin-4-yl)oxy)-6-methoxy In a mixture of N-methyl-1H-indole-1-carboxamide (40mg, 0.128mmol) and N,N-dimethylformamide (0.5mL). The previously prepared tetrahydrofuran solution of the acid chloride was added at the same temperature, and the mixture was stirred at room temperature for 80 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and ethyl acetate for fractionation, and the organic layer was dried over anhydrous sodium sulfate. The resultant was filtered through NH silica gel (ethyl acetate) and then concentrated under vacuum to obtain a crude product (80.6 mg).

This crude product (80.6 mg) was dissolved in N,N-dimethylformamide (0.7 mL), commercially available 4-hydroxypiperidine (93 mg, 0.919 mmol) was added at room temperature under nitrogen atmosphere, and The mixture was heated and stirred at 80°C for 12 hours. The mixture was cooled to room temperature, water and ethyl acetate were added to the reaction mixture for fractionation, and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with water and a saturated saline solution, then dried over anhydrous sodium sulfate, and then filtered. The solvent was evaporated, and the obtained residue was purified by NH silica gel TLC (ethyl acetate:methanol=9:1). The obtained residue was purified by NH silica gel TLC (ethyl acetate) to obtain the title compound (10.8 mg, 30%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.55-1.67 (2H, m), 1.86-1.97 (2H, m), 2.31 (2H, t, J=9.5Hz), 2.78-2.92 (4H, m), 3.06(3H, d, J=4.4Hz), 3.67-3.77(1H, m), 3.86(3H, s), 4.14(2H, t, J=5.7Hz), 5.50-5.59(1H, m ), 6.54 (1H, d, J = 3.3Hz), 6.60 (1H, dd, J = 5.7, 2.4Hz), 6.95 (2H, d, J = 8.8Hz), 7.22 (1H, d, J = 3.7Hz ), 7.32(1H, s), 7.81(2H, d, J=8.8Hz), 7.88(1H, d, J=1.8Hz), 8.03(1H, s), 8.09(1H, d, J=5.9Hz ), 8.47 (1H, brs).

The reagent 4-(2-chloroethoxy)benzoic acid was synthesized by the following method.

[Production Example 12-1] 4-(2-Chloroethoxy)benzoic acid

[chemical formula 71]

Potassium carbonate (7.27 g, 52.6 mmol) and commercially available 1-chloro-2-iodoethane (3.6 mL, 39.5 mmol) were added to commercially available methyl p-hydroxybenzoate at room temperature under nitrogen atmosphere ester (2.0 g, 13.1 mmol) and N,N-dimethylformamide (50 mL), and the mixture was heated and stirred at 60° C. for 12 hours. The mixture was cooled to room temperature, and then saturated aqueous ammonium chloride solution, water and diethyl ether were added to the reaction mixture for segmentation. The organic layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and then filtered and concentrated under vacuum. To the residue were added tetrahydrofuran (25 mL), methanol (10 mL), and 2M sodium hydroxide solution (10 mL) at room temperature, and the mixture was heated and stirred at 80° C. for 4 hr. The reaction mixture was cooled to 0 °C, acidified with 5M hydrochloric acid, and the mixture was then diluted with ethyl acetate for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, the precipitate was isolated by filtration with a liquid mixture of ethyl acetate and tetrahydrofuran, the resultant was washed, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1-2:1-1:1), and the target fraction was concentrated in vacuo to obtain the title compound (278mg, 11% ).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.92-3.98 (2H, m), 4.26-4.35 (2H, m), 6.96-7.06 (2H, m), 7.82-7.91 (2H, m ), 12.68 (1H, brs).

[Example 13]

5-((2-(1-(1-ethylpiperidin-4-yl)-1H-pyrazole-4-carboxamide)pyridin-4-yl)oxy)-6-methoxy-N- Methyl-1H-indole-1-carboxamide

[chemical formula 72]

Acetaldehyde (8.9 mg, 0.202 mmol) and sodium triacetoxyborohydride (43.9 mg, 0.207 mmol) were added to 6-methoxy-N-methyl- 5-((2-(1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (20.3mg , 0.041 mmol) and tetrahydrofuran (1.0 mL), and the mixture was stirred for 2.5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated and the resulting residue was purified by NH silica gel TLC (ethyl acetate). The product was washed with diethyl ether to obtain the title compound (9.3 mg, 43%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.11 (3H, t, J=7.1Hz), 1.94-2.24 (6H, m), 2.46 (2H, q, J=7.4Hz), 3.03-3.11 (5H, m), 3.86 (3H, s), 4.09-4.19 (1H, m), 5.49-5.56 (1H, m), 6.54 (1H, d, J=2.9Hz), 6.60 (1H, dd, J =5.9, 2.4Hz), 7.22 (1H, d, J = 3.7Hz), 7.31 (1H, s), 7.81 (1H, d, J = 2.0Hz), 7.85 (1H, d, J = 0.7Hz), 7.96 (1H, s), 8.02 (1H, s), 8.08 (1H, d, J=5.9Hz), 8.17 (1H, brs).

The starting material 6-methoxy-N-methyl-5-((2-(1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide)pyridine-4-yl) was synthesized by base)oxy)-1H-indole-1-carboxamide.

[Production example 13-1]

tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[chemical formula 73]

Commercially available methanesulfonyl chloride (6.35 mL, 82.0 mmol) and triethylamine (26.0 mL, 186 mmol) were added to commercially available tert-butyl 4-hydroxy-1-piperidinecarboxylate (15 g , 74.5 mmol) and tetrahydrofuran (200 mL), and the mixture was stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was dried and filtered by conventional means. The solvent was evaporated, and the residue was collected by filtration and washed with n-heptane to obtain the title compound (19.8 g, 95%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.46 (9H, s), 1.72-1.88 (2H, m), 1.90-2.04 (2H, m), 3.03 (3H, s), 3.24-3.36 ( 2H, m), 3.64-3.77 (2H, m), 4.80-4.94 (1H, m).

[Production example 13-2]

tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[chemical formula 74]

tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2.7 g, 9.67 mmol) described in Example 13-1 and commercially available ethyl 4-pyrazolecarboxylate ( 1.49g, 10.6mmol) was dissolved in N,N-dimethylformamide (30mL), 50%-72% oily sodium hydride (570mg) was added at 0°C, and the mixture was heated and stirred at 60°C 11 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added for partitioning. The organic layer was washed twice with water, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1-1:3-0:1) Purified, and concentrated the target fractions under vacuum to obtain the title compound (2.11 g, 68%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.34 (3H, t, J=7.1Hz), 1.47 (9H, s), 1.82-1.96 (2H, m), 2.10-2.18 (2H, m) , 2.82-2.96 (2H, m), 4.19-4.34 (3H, m), 4.29 (2H, q, J=7.1Hz), 7.91 (1H, s), 7.92 (1H, s).

[Production example 13-3]

1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid

[chemical formula 75]

tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.11 g, 6.53 mmol) described in Production Example 13-2 was dissolved in methanol ( 60 mL), potassium hydroxide (1.46 g, 26.1 mmol) dissolved in water (16 mL) was then added, and the mixture was then stirred for 27 hours. The reaction mixture was concentrated under vacuum and diethyl ether was added for fractionation. Ethyl acetate was added to the aqueous layer for dilution, then 5% aqueous potassium hydrogensulfate solution was added for acidification, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated to obtain the title compound (1.58 g, 82%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.48 (9H, s), 1.84-1.98 (2H, m), 2.11-2.20 (2H, m), 2.81-2.97 (2H, m), 4.18- 4.36 (3H, m), 7.97 (1H, s), 7.98 (1H, s).

[Production example 13-4]

6-methoxy-N-methyl-5-((2-(1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide)pyridin-4-yl)oxy)-1H -Indole-1-carboxamide

[chemical formula 76]

Benzotriazole (97 mg, 0.813 mmol) was dissolved in dichloromethane (4.0 mL), and thionyl chloride (59 μL, 0.813 mmol) was added at room temperature, and the mixture was stirred under nitrogen atmosphere for 5 minutes. To the reaction mixture was added 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid (200 mg , 0.677 mmol), and the mixture was stirred for 25 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate, and then the anhydrous sodium sulfate was washed with dichloromethane, and the filtrate was added to the mixture prepared in Production Example 1-6 at 0°C. 5-((2-aminopyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole-1-carboxamide (102mg, 0.327mmol), triethylamine ( 0.453 mL, 3.27 mmol), and 4-dimethylaminopyridine (3.99 mg, 0.033 mmol) in a mixture of tetrahydrofuran (5.0 mL). The mixture was stirred at room temperature for 2 hours, then water and ethyl acetate were added to the reaction mixture for segmentation, and then the organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under vacuum. The residue was dissolved in tetrahydrofuran, an excess of 9.8M methylamine methanol solution was added at room temperature, and the mixture was stirred for 4 hrs. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:9-0: 1) Purify. The target fractions were concentrated under vacuum to obtain a crude product (170mg).

The crude product (170 mg) was dissolved in dichloromethane (1.8 mL), and trifluoroacetic acid (0.5 mL) was added at 0°C. The mixture was stirred at room temperature for 80 minutes, then concentrated in vacuo, and the residue was dissolved in dichloromethane-triethylamine, and the resultant was subjected to NH silica gel column chromatography (ethyl acetate:methanol= 49:1-4:1), then the target fractions were concentrated in vacuo to obtain the title compound (81.2 mg, 51%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.78-1.91 (2H, m), 2.11-2.19 (2H, m), 2.75 (2H, td, J = 12.3, 2.3Hz), 3.05 (3H, d, J=4.6Hz), 3.19-3.27(2H, m), 3.85(3H, s), 4.16-4.26(1H, m), 5.53-5.63(1H, m), 6.53(1H, d, J= 3.5Hz), 6.60(1H, dd, J=5.8, 2.5Hz), 7.22(1H, d, J=3.8Hz), 7.30(1H, s), 7.81(1H, d, J=2.4Hz), 7.86 (1H, s), 7.96 (1H, s), 8.03 (1H, s), 8.08 (1H, d, J=5.9Hz), 8.22 (1H, brs).

[Example 14]

5-((2-(4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)benzamide)pyridin-4-yl)oxy)-6-methoxy- N-Methyl-1H-indole-1-carboxamide

[chemical formula 77]

Benzotriazole (34.1 mg, 0.286 mmol) was dissolved in dichloromethane (1.5 mL), then thionyl chloride (20 μL, 0.274 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was then stirred for 5 minutes . To the reaction mixture was added 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid (79.3 mg, 0.247 mg) described in Production Example 14-1 at room temperature mmol), and the mixture was stirred for 25 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate, and then the anhydrous sodium sulfate was washed with dichloromethane, and then the filtrate was added to the The 5-((2-aminopyridin-4-yl)oxy)-6-methoxy-N-methyl-1H-indole-1-carboxamide (35.6mg, 0.114mmol), triethyl Amine (0.158 mL, 1.14 mmol), and 4-dimethylaminopyridine (1.39 mg, 0.011 mmol) in a mixture in tetrahydrofuran (1.1 mL). The reaction mixture was stirred at room temperature for 1.5 hours, then water and ethyl acetate were added to the reaction mixture for segmentation, and then the organic layer was washed with saturated saline solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was concentrated in vacuo, the residue was dissolved in tetrahydrofuran, an excess of 9.8M methanolic methylamine was added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under vacuum, the residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:3-0:1 ) for purification. The target fractions were concentrated under vacuum to obtain a crude product A (41.1 mg).

The crude product A (41.1 mg) was dissolved in dichloromethane (0.6 mL), and trifluoroacetic acid (0.2 mL) was added at 0°C. The mixture was stirred at room temperature for 75 minutes, and the resultant was concentrated under vacuum, the residue was dissolved in dichloromethane-triethylamine, and then the resultant was subjected to NH silica gel column chromatography (ethyl acetate :methanol=49:1-4:1), and then the target fraction was concentrated under vacuum to obtain a crude product B (34 mg).

To a mixture of crude product B (8.5 mg, 0.016 mmol) and tetrahydrofuran (0.5 mL) were added sodium triacetoxyborohydride (17.5 mg, 0.082 mmol) and commercially available 2-glycolaldehyde at room temperature (4.95 mg, 0.082 mmol), and the mixture was stirred for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated and the resulting residue was purified by NH silica gel TLC (ethyl acetate). The residue was washed with diethyl ether to obtain the title compound (6.4 mg, 40%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.78-1.90 (2H, m), 1.95-2.06 (2H, m), 2.35-2.47 (2H, m), 2.57 (2H, t, J=5.6 Hz), 2.72-2.83(2H, m), 3.07(3H, d, J=4.4Hz), 3.62(2H, t, J=5.3Hz), 3.86(3H, s), 4.38-4.48(1H, m ), 5.45-5.54 (1H, m), 6.55 (1H, d, J=3.7Hz), 6.59 (1H, dd, J=5.7, 2.4Hz), 6.94 (2H, d, J=8.8Hz), 7.23 (1H, d, J = 3.7Hz), 7.32 (1H, s), 7.81 (2H, d, J = 8.8Hz), 7.89 (1H, d, J = 2.6Hz), 8.03 (1H, s), 8.09 (1H, d, J = 5.5 Hz), 8.45 (1H, brs).

The starting material 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid was synthesized by the following method.

[Production example 14-1]

4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid

[chemical formula 78]

At 0°C, to commercially available benzyl 4-hydroxybenzoate (3 g, 13.1 mmol), commercially available tert-butyl 4-hydroxypiperidine-1-carboxylate (2.77 g, 13.8 mmol), triphenyl Diisopropyl azodicarboxylate (9.65 mL, 1.9 M, 18.3 mmol) was added to a mixture of phosphine (4.81 g, 18.3 mmol), and tetrahydrofuran (150 mL), and the mixture was stirred overnight at room temperature . Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, the resulting residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1), and the target fraction was concentrated under vacuum to obtain a crude product (3.8 g).

A part of this crude product (500 mg, 1.22 mmol) was dissolved in ethanol (5 mL), 5M sodium hydroxide solution (0.729 mL, 3.65 mmol) was added, and the mixture was heated and stirred at 50° C. for 7 hr. The reaction mixture was cooled to room temperature, and then 5M hydrochloric acid and ethyl acetate were added for fractionation. The organic layer was dried and filtered by conventional means. The solvent was evaporated, and then the resultant was collected by filtration and washed with n-heptane to obtain the title compound (343 mg, 62%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.47 (9H, s), 1.65-1.84 (2H, m), 1.87-2.07 (2H, m), 3.30-3.51 (2H, m), 3.60- 3.80 (2H, m), 4.50-4.66 (1H, m), 6.87-7.03 (2H, m), 7.98-8.14 (2H, m).

[Example 15]

6-ethoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-methanol Amide

[chemical formula 79]

The 4-(4-((4-((6-ethoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine described in Example 15-8 will be produced -2-yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (3.35g, 5.46mmol) was dissolved in dichloromethane (45mL) and trifluoroacetic acid (15ml) was added at 0°C . The mixture was stirred at room temperature for 110 minutes, then concentrated in vacuo, and the residue was dissolved in dichloromethane-triethylamine, and the resultant was subjected to NH silica gel column chromatography (ethyl acetate:methanol= 97:3-4:1) to obtain the title compound (2.41 g, 86%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.25 (3H, t, J=7.0Hz), 1.50-1.70 (2H, m), 1.79-1.88 (2H, m), 2.63-2.80 (3H, m), 3.06(3H, d, J=4.8Hz), 3.16-3.24(2H, m), 4.11(2H, q, J=7.0Hz), 5.46-5.54(1H, m), 6.55(1H, d , J = 3.3Hz), 6.60 (1H, dd, J = 5.9, 2.6Hz), 7.23 (1H, d, J = 3.7Hz), 7.29-7.34 (3H, m), 7.78-7.83 (2H, m) , 7.92 (1H, d, J=2.2Hz), 8.00 (1H, s), 8.08-8.11 (1H, m), 8.50 (1H, brs).

The starting material 4-(4-((4-((6-ethoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine-2-yl) was synthesized by yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[Production Example 15-1]

4-Ethoxy-3-hydroxybenzaldehyde

[chemical formula 80]

Commercially available 3,4-dihydroxybenzaldehyde (35.8 g, 259 mmol) and potassium carbonate (37.6 g, 272 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then heated at 0 °C Commercially available ethyl iodide (22 mL, 275 mmol) was added under nitrogen atmosphere, and then the mixture was stirred for 2 days. The solvent was evaporated under vacuum, the resultant was cooled to 0 °C, and then 5M hydrochloric acid, ethyl acetate and water were added for fractionation. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed twice with water and then with a saturated saline solution, and the mixture was dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated, then dichloromethane was added, and the precipitate was then collected by filtration to obtain the title compound (25.8 g, 60%). The filtrate was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-1:1). The target fraction was concentrated under vacuum, then diethyl ether and dichloromethane were added to the residue, and the precipitate was collected by filtration to obtain the title compound (3.45 g, 8.0%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.50 (3H, t, J = 7.1Hz), 4.22 (2H, q, J = 7.0Hz), 5.75 (1H, s), 6.95 (1H, d , J=8.1Hz), 7.39-7.45 (2H, m), 9.84 (1H, s).

[Production example 15-2]

3-(Benzyloxy)-4-ethoxybenzaldehyde

[chemical formula 81]

Potassium carbonate (19.8 g, 143 mmol) and benzyl chloride (16.5 mL, 143 mmol) were added to 4-ethoxy-3-hydroxybenzaldehyde ( 20 g, 120 mmol) in ethanol (200 mL), and the mixture was heated and stirred at 90° C. for 2.5 hours. The mixture was cooled to 0 °C and 2M hydrochloric acid, ethyl acetate and water were added for fractionation. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-3:1). The target fractions were concentrated in vacuo to obtain the title compound (28.5 g, 92%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.51 (3H, t, J = 7.0Hz), 4.20 (2H, q, J = 7.0Hz), 5.19 (2H, s), 6.98 (1H, d , J=8.8Hz), 7.29-7.34 (1H, m), 7.35-7.41 (2H, m), 7.43-7.49 (4H, m), 9.81 (1H, s).

[Production Example 15-3]

(E)-2-(Benzyloxy)-1-ethoxy-4-(2-nitrovinyl)benzene

[chemical formula 82]

3-(Benzyloxy)-4-ethoxybenzaldehyde (14.5 g, 56.4 mmol) described in Production Example 15-2 was dissolved in acetic acid (45 mL), and then acetic acid was added at room temperature under nitrogen atmosphere Ammonium (5.22 g, 67.7 mmol) and nitromethane (7.5 mL, 138 mmol), and the mixture was heated and stirred at 130° C. for 2.5 hours. The mixture was cooled to room temperature, and the precipitate was collected by filtration and washed with ethanol to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.50 (3H, t, J = 7.0Hz), 4.17 (2H, q, J = 7.2Hz), 5.17 (2H, s), 6.92 (1H, d , J = 8.4Hz), 7.04 (1H, d, J = 2.2Hz), 7.16 (1H, dd, J = 8.6, 2.0Hz), 7.29-7.51 (6H, m), 7.90 (1H, d, J = 13.5Hz).

[Production example 15-4]

6-Ethoxy-1H-indol-5-ol

[chemical formula 83]

Fuming nitric acid (13 mL, 289 mmol) was slowly added to (E)-2-(benzyloxy)-3-ethoxy-4-(2-nitroethylene) described in Production Example 15-3 at room temperature (16.9 g, 56.6 mmol) and acetic acid (160 mL), and the mixture was stirred for 6 hours. The reaction mixture was poured onto ice, and the precipitate was collected by filtration, and then washed with a liquid mixture of acetic acid and ethanol to obtain a crude product (19.5 g).

The crude product (19.5 g) was suspended in methanol (500 mL), then 10% palladium-carbon (water content, 50%) (6.85 g) was added, and the mixture was stirred under a hydrogen atmosphere for 17 hr. The catalyst was filtered off through celite and the resultant was washed with methanol. The filtrate was concentrated under vacuum, and the resultant was dissolved in tetrahydrofuran and absorbed by silica gel. The adsorbed silica gel was concentrated under vacuum, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-13:7). The target fractions were concentrated under vacuum, and the residue was collected by filtration and washed with diethyl ether to obtain the title compound (3.78 g, 38%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.48 (3H, t, J = 6.9Hz), 4.13 (2H, q, J = 6.8Hz), 5.50 (1H, s), 6.39-6.43 (1H , m), 6.87 (1H, s), 7.05-7.09 (1H, m), 7.13 (1H, s), 7.91 (1H, brs).

[Production Example 15-5]

N-(4-((6-ethoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide

[chemical formula 84]

Under a nitrogen atmosphere, 6-ethoxy-1H-indol-5-ol (7.0 g, 39.5 mmol) described in Production Example 15-4 was dissolved in dimethylsulfoxide (40 mL), and then N-(4-chloropyridin-2-yl)acetamide (8.09g, 47.4mmol) described in Production Example 1-5, and potassium tert-butoxide (4.88g, 43.5mmol) were added below, and the mixture was Heat and stir at 160°C for 4 hours. The reaction liquid was cooled to room temperature, and water and ethyl acetate were added for segmentation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed twice with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=3:1-2:1-3:2-1:3-1:4-0 : 1) was purified, and then the target fraction was concentrated under vacuum to obtain the title compound (7.16 g, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.23 (3H, t, J = 7.0Hz), 2.14 (3H, s), 4.02 (2H, q, J = 7.0Hz), 6.46-6.49 (1H , m), 6.54 (1H, dd, J=5.9, 2.2Hz), 7.01 (1H, s), 7.13-7.16 (1H, m), 7.35 (1H, s), 7.74 (1H, brs), 7.87 ( 1H, brs), 8.02 (1H, d, J = 5.9 Hz), 8.10 (1H, brs).

[Production Example 15-6]

4-((6-ethoxy-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 85]

N-(4-((6-ethoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide (7.16 g, 23.0 mmol) described in Example 15-5 will be produced It was dissolved in methanol (50 mL), 2M sodium hydroxide solution (50 mL) was added at room temperature under nitrogen atmosphere, and the mixture was heated and stirred at 75° C. for 2.5 hrs. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added for segmentation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the resultant was filtered and concentrated under vacuum. A liquid mixture of diethyl ether and ethyl acetate was added to the residue, and the mixture was collected by filtration and washed to obtain the title compound (5.35 g, 86%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.28 (3H, t, J = 7.0Hz), 4.02 (2H, q, J = 7.0Hz), 4.28 (2H, brs), 5.91 (1H, d , J=2.2Hz), 6.29(1H, dd, J=5.9, 2.2Hz), 6.46-6.50(1H, m), 7.00(1H, s), 7.15-7.18(1H, m), 7.33(1H, s), 7.88 (1H, d, J = 5.9 Hz), 8.13 (1H, brs).

[Production example 15-7]

5-((2-aminopyridin-4-yl)oxy)-6-ethoxy-N-methyl-1H-indole-1-carboxamide

[chemical formula 86]

4-((6-Ethoxy-1H-indol-5-yl)oxy)pyridin-2-amine (6.44 g, 23.9 mmol) described in Production Example 15-6 was dissolved in N,N- To dimethylformamide (80 mL) was added 50%-72% oily sodium hydride (1.41 g) at 0°C under nitrogen atmosphere, and the mixture was stirred at room temperature for 40 minutes. The mixture was cooled to 0°C again, methyl phenylcarbamate (5.78 g, 38.3 mmol) described in Production Example 1-7 was added, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added saturated aqueous ammonium chloride, water and ethyl acetate for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed twice with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. A liquid mixture of diethyl ether and ethyl acetate was added to the residue, then the precipitate was collected by filtration, and the resultant was washed with ethyl acetate again to obtain the title compound (4.24 g, 54%). The filtrate was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-9:1), the target fraction was concentrated in vacuo, and then the residue was collected by filtration and washed with diethyl ether and ethyl acetate A liquid mixture of esters was washed to obtain the title compound (1.58 g, 20%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.29 (3H, t, J=7.0Hz), 3.07 (3H, d, J=4.8Hz), 4.09 (2H, q, J=7.0Hz), 4.29 (2H, brs), 5.42-5.51 (1H, m), 5.90 (1H, d, J = 2.2Hz), 6.27 (1H, dd, J = 6.2, 2.2Hz), 6.55 (1H, dd, J = 3.7, 0.7Hz), 7.23 (1H, d, J = 3.7Hz), 7.27 (1H, s), 7.89 (1H, d, J = 5.9Hz), 7.98 (1H, s).

[Production example 15-8]

4-(4-((4-((6-ethoxy-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)benzene Base) tert-butyl piperidine-1-carboxylate

[chemical formula 87]

Benzotriazole (1.92 g, 16.1 mmol) was dissolved in dichloromethane (80 mL), thionyl chloride (1.15 mL, 15.8 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (4.1 g, 13.4 mmol) described in Production Example 1-12 at room temperature, and The mixture was stirred for 25 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate and then the anhydrous sodium sulfate was washed with dichloromethane, and the filtrate was added at 0°C to the 5-((2-aminopyridin-4-yl)oxy)-6-ethoxy-N-methyl-1H-indole-1-carboxamide (2g, 6.13mmol), triethylamine (8.5 mL, 61.3 mmol), and 4-dimethylaminopyridine (75 mg, 0.613 mmol) in a mixture of tetrahydrofuran (40 mL). The mixture was stirred at room temperature for 14 hours, then water and ethyl acetate were added to the reaction mixture for partitioning. The organic layer was washed with a saturated saline solution, and the resultant was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was dissolved in tetrahydrofuran, an excess of 9.8M methylamine in methanol was added at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was concentrated under vacuum, dichloromethane was added to the residue, and diethyl ether and ethyl acetate were further added, and the product was then collected by filtration and washed to obtain the title compound (3.08 g, 82%) . The filtrate was concentrated under vacuum, and the resultant was dissolved in dichloromethane and purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:9). The target fractions were concentrated in vacuo to obtain the title compound (273 mg, 7.3%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.25 (3H, t, J=7.0Hz), 1.48 (9H, s), 1.50-1.70 (2H, m), 1.78-1.87 (2H, m) , 2.64-2.87(3H, m), 3.07(3H, d, J=4.8Hz), 4.11(2H, q, J=7.0Hz), 4.16-4.33(2H, m), 5.45-5.52(1H, m ), 6.55 (1H, d, J = 3.6Hz), 6.60 (1H, dd, J = 5.9, 2.3Hz), 7.23 (1H, d, J = 3.7Hz), 7.28-7.33 (3H, m), 7.79 -7.83 (2H, m), 7.92 (1H, d, J=2.2Hz), 8.00 (1H, s), 8.09 (1H, d, J=5.9Hz), 8.51 (1H, brs).

[Example 16]

6-ethoxy-5-((2-(4-(1-ethylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-N-methyl-1H-indole -1-formamide

[chemical formula 88]

Sodium triacetoxyborohydride (1.36 g, 6.43 mmol) was added to 6-ethoxy-N-methyl-5-((2-(4-(piperidine- 4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (2.2g, 4.28mmol) in a mixture of tetrahydrofuran (33mL), then added commercially available acetaldehyde (283 mg, 6.43 mmol) in tetrahydrofuran (11 mL), and then the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated and the residue thus obtained was combined with 6-ethoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzene) from a similar starting material by a similar method. Carboxamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (200mg, 0.389mmol) The residues obtained were combined. Ethyl acetate was added to the combined residues, and the product was collected by filtration to obtain the title compound (2.20 g, 87%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.15 (3H, t, J = 7.2Hz), 1.25 (3H, t, J = 7.0Hz), 1.82-1.92 (4H, m), 2.01-2.13 (2H, m), 2.43-2.62 (3H, m), 3.04 (3H, d, J=4.6Hz), 3.08-3.17 (2H, m), 4.10 (2H, q, J=6.8Hz), 5.55- 5.62(1H, m), 6.53(1H, d, J=3.7Hz), 6.60(1H, dd, J=5.7, 2.2Hz), 7.23(1H, d, J=3.7Hz), 7.30-7.35(3H , m), 7.79 (2H, d, J = 8.2Hz), 7.91 (1H, d, J = 2.2Hz), 8.00 (1H, s), 8.09 (1H, d, J = 5.7Hz), 8.53 (1H , brs).

[Example 17]

6-isopropoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1- Formamide

[chemical formula 89]

Benzotriazole (88.7 mg, 0.745 mmol) was dissolved in dichloromethane (4.0 mL), thionyl chloride (52 μL, 0.707 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (180 mg, 0.589 mmol) described in Production Example 1-12 at room temperature, and The mixture was stirred for 55 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate and then the anhydrous sodium sulfate was washed with dichloromethane, and the filtrate was added at 0°C to the 5-((2-aminopyridin-4-yl)oxy)-6-isopropoxy-N-methyl-1H-indole-1-carboxamide (77mg, 0.226mmol), triethylamine ( 0.314mL, 2.26mmol), and 4-dimethylaminopyridine (2.76mg, 0.023mmol) in tetrahydrofuran (2.0mL), dichloromethane (5.0mL), and N, N-dimethylformamide (0.2mL ) in a mixture. The mixture was stirred at room temperature for 140 minutes, and then water and ethyl acetate were added to the reaction mixture for segmentation. The organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, the residue was dissolved in tetrahydrofuran, excess methylamine tetrahydrofuran solution was added at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under vacuum, the residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:3-0:1 ) and the target fractions were concentrated in vacuo to obtain a crude product (111 mg).

The crude product (111 mg) was dissolved in dichloromethane (1.8 mL), and trifluoroacetic acid (0.65 mL) was added at 0°C. The mixture was stirred at room temperature for 90 minutes, and then concentrated under vacuum, the residue was dissolved in dichloromethane-triethylamine, and the resultant was then subjected to NH silica gel column chromatography (ethyl acetate:methanol =1:0-17:3-4:1) to obtain the title compound (85.4 mg, 92%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.22 (6H, d, J=6.0Hz), 1.55-1.71 (2H, m), 1.79-1.88 (2H, m), 2.62-2.80 (3H, m), 3.05(3H, d, J=4.8Hz), 3.15-3.25(2H, m), 4.52-4.64(1H, m), 5.49-5.57(1H, m), 6.54(1H, d, J= 3.7Hz), 6.58(1H, dd, J=5.7, 2.4Hz), 7.24(1H, d, J=3.8Hz), 7.29-7.35(3H, m), 7.80(2H, d, J=8.2Hz) , 7.93 (1H, d, J = 2.4Hz), 8.01 (1H, s), 8.08 (1H, d, J = 5.9Hz), 8.51 (1H, brs).

The starting material 5-((2-aminopyridin-4-yl)oxy)-6-isopropoxy-N-methyl-1H-indole-1-carboxamide was synthesized by the following method.

[Production Example 17-1]

3-Hydroxy-4-isopropoxybenzaldehyde

[chemical formula 90]

Commercially available 3,4-dihydroxybenzaldehyde (5 g, 36.2 mmol) and potassium carbonate (5.15 g, 37.3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and then at room temperature in 2-Bromopropane (3.5 mL, 37.3 mmol) was added under nitrogen atmosphere, and the mixture was heated and stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to 0 °C, and then 2M hydrochloric acid, ethyl acetate and water were added for segmentation. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with water and a saturated saline solution, and the resultant was dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated, dichloromethane was added to the residue, the precipitate was isolated by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1-13:7), and then the target fraction was concentrated in vacuo to obtain the title compound (1.84 g, 28%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.42 (6H, d, J=5.9Hz), 4.73 (1H, spt, J=6.1Hz), 5.78 (1H, s), 6.95 (1H, d , J=8.1 Hz), 7.41 (1H, dd, J=8.2, 2.0 Hz), 7.44 (1H, d, J=1.8 Hz), 9.83 (1H, s).

[Production example 17-2]

3-(Benzyloxy)-4-isopropoxybenzaldehyde

[chemical formula 91]

Potassium carbonate (1.83 g, 13.2 mmol) and benzyl chloride (1.55 mL, 13.5 mmol) were added to 3-hydroxy-4-isopropoxyl as described in Production Example 17-1 at room temperature under nitrogen atmosphere Benzaldehyde (1.84 g, 10.2 mmol) was suspended in ethanol (20 mL), and the mixture was heated and stirred at 90° C. for 2 hours. The mixture was cooled to 0°C, and then 2M hydrochloric acid, ethyl acetate and water were added for fractionation. The organic layer was washed with a saturated saline solution, and the resultant was dried over anhydrous sodium sulfate and then filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1-3:1). The target fractions were concentrated in vacuo to obtain the title compound (2.59 g, 94%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.42 (6H, d, J = 6.0HZ), 4.69 (1H, spt, J = 6.1HZ), 5.18 (2H, s), 7.00 (1H, d , J=8.1Hz), 7.29-7.41 (3H, m), 7.43-7.48 (4H, m), 9.81 (1H, s).

[Production example 17-3]

(E)-2-(Benzyloxy)-1-isopropoxy-4-(2-nitrovinyl)benzene

[chemical formula 92]

3-(Benzyloxy)-4-isopropoxybenzaldehyde (2.59 g, 9.59 mmol) described in Production Example 17-2 was dissolved in acetic acid (7.5 mL), and then at room temperature under nitrogen atmosphere Ammonium acetate (887 mg, 11.5 mmol) and nitromethane (1.25 mL, 23.1 mmol) were added, and the mixture was heated and stirred at 130°C for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filtration and washed with ethanol to obtain the title compound (2.20 g, 73%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.41 (6H, d, J = 6.2Hz), 4.55-4.71 (1H, m), 5.15 (2H, s), 6.94 (1H, d, J = 8.4HZ), 7.05(1H, d, J=1.8Hz), 7.15(1H, dd, J=8.4, 1.8 Hz), 7.29-7.48(6H, m), 7.90(1H, d, J=13.5Hz) .

[Production example 17-4]

6-Isopropoxy-1H-indol-5-ol

[chemical formula 93]

At room temperature, fuming nitric acid (1.5 mL, 33.3 mmol) was slowly added to (E)-2-(benzyloxy)-1-isopropoxy-4-(2- nitrovinyl)benzene (2.20 g, 7.02 mmol) and acetic acid (20 mL), and the mixture was stirred for 7.5 hours. The reaction mixture was poured onto ice, the precipitate was collected by filtration, and then the resultant was washed with a liquid mixture of acetic acid and ethanol to obtain a crude product (2.28 g).

The crude product (2.28 g) was suspended in methanol (60 mL), 10% palladium-carbon (water content, 50%) (677 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 14.5 hr. The catalyst was filtered off through celite and the resultant was washed with methanol. The filtrate was concentrated under vacuum, and purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2). The target fractions were concentrated in vacuo to obtain the title compound (475 mg, 35%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40 (6H, d, J = 6.2Hz), 4.57 (1H, spt, J = 6.1Hz), 5.55 (1H, s), 6.38-6.44 (1H , m), 6.90 (1H, s), 7.08 (1H, t, J=2.7Hz), 7.13 (1H, s), 7.90 (1H, brs).

[Production Example 17-5]

N-(4-((6-isopropoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide

[chemical formula 94]

Under a nitrogen atmosphere, 6-isopropoxy-1H-indol-5-ol (165 mg, 0.863 mmol) described in Example 17-4 and N-(4 -Chloropyridin-2-yl)acetamide (442 mg, 2.59 mmol) was dissolved in dimethylsulfoxide (2.0 mL), then potassium tert-butoxide (194 mg, 1.73 mmol) was added at room temperature, and the mixture was heated and Stir at 160°C for 3 hours. The reaction liquid was cooled to room temperature, and water and ethyl acetate were added for segmentation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=3:2-1:3), and then the target fraction was concentrated in vacuo to obtain The title compound (116 mg, 41%) was obtained.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.21 (6H, d, J=6.2Hz), 2.14 (3H, s), 4.34-4.48 (1H, m), 6.45-6.53 (2H, m) , 7.03 (1H, s), 7.16 (1H, t, J=2.7Hz), 7.35 (1H, s), 7.77 (1H, brs), 7.85-8.05 (2H, m), 8.10 (1H, brs).

[Production example 17-6]

4-((6-isopropoxy-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 95]

N-(4-((6-isopropoxy-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide (116 mg, 0.357 mmol) described in Example 17-5 will be produced This was dissolved in methanol (2.5 mL), 28% sodium methoxide (0.728 mL) was added at room temperature under nitrogen atmosphere, and the mixture was heated and stirred at 70° C. for 3 hr. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added for segmentation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the resultant was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-9:1) After purification, the target fractions were concentrated in vacuo to obtain the title compound (66.3 mg, 66%). ¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.22 (6H, d, J = 5.9 Hz), 4.28 (2H, brs), 4.36-4.47 (1H, m), 5.89 (1H, d, J = 2.2Hz), 6.29(1H, dd, J=5.9, 2.2Hz), 6.46-6.51(1H, m), 7.04(1H, s), 7.18(1H, t, J=2.9Hz), 7.34(1H, s), 7.88 (1H, d, J = 5.9 Hz), 8.12 (1H, brs).

[Production example 17-7]

5-((2-aminopyridin-4-yl)oxy)-6-isopropoxy-N-methyl-1H-indole-1-carboxamide

[chemical formula 96]

4-((6-isopropoxy-1H-indol-5-yl)oxy)pyridin-2-amine (65.6 mg, 0.232 mmol) described in Production Example 17-6 was dissolved in N,N - Dimethylformamide (1.5 mL) and 50%-72% oily sodium hydride (16.7 mg) was added at 0°C under nitrogen atmosphere, and the mixture was stirred at room temperature for 50 minutes. The mixture was cooled to 0°C again, methyl phenylcarbamate (69.2 mg, 0.458 mmol) described in Production Example 1-7 was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added saturated aqueous ammonium chloride, water and ethyl acetate for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water, and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-19:1 ) was purified, then the target fraction was concentrated in vacuo to obtain the title compound (77.0 mg, 98%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.24 (6H, d, J = 6.0Hz), 3.06 (3H, d, J = 4.8Hz), 4.32 (2H, brs), 4.56 (1H, spt , J=6.1Hz), 5.50-5.61(1H, m), 5.89(1H, d, J=2.2Hz), 6.27(1H, dd, J=5.9, 2.2Hz), 6.55(1H, dd, J= 3.6, 0.6Hz), 7.24-7.28 (2H, m), 7.88 (1H, d, J=5.9Hz), 8.00 (1H, s).

[Example 18]

(R)-5-((2-(4-(1-(2-hydroxypropyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-isopropoxy -N-Methyl-1H-indole-1-carboxamide

[chemical formula 97]

Commercially available (R)-(+)-propylene oxide (20.5 mg, 0.353 mmol) was added to 6-isopropoxy-N-methyl-5-((2-(4 -(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (12.7 mg, 0.024 mmol) and ethanol (0.5 mL) in a mixture , and the mixture was heated and stirred at 80° C. for 3 hours and 40 minutes with a sealed tube. The mixture was cooled to room temperature, then the reaction mixture was concentrated in vacuo, the obtained residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1: 4-0:1-ethyl acetate:methanol=99:1-19:1) for purification. The target fractions were concentrated under vacuum, and the precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (8.28 mg, 59%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.15 (3H, d, J=6.2Hz), 1.22 (6H, d, J=6.2Hz), 1.70-1.90 (3H, m), 2.00-2.09 (1H, m), 2.21-2.46 (3H, m), 2.53-2.64 (1H, m), 2.92 (1H, d, J = 11.0Hz), 3.07 (3H, d, J = 4.8Hz), 3.14 ( 1H, d, J=11.3Hz), 3.80-3.91(1H, m), 4.53-4.64(1H, m), 5.44-5.52(1H, m), 6.55(1H, d, J=3.3Hz), 6.58 (1H, dd, J=5.7, 2.4Hz), 7.25(1H, d, J=3.7Hz), 7.30-7.36(3H, m), 7.81(2H, d, J=8.4Hz), 7.93(1H, d, J = 2.2 Hz), 8.01 (1H, s), 8.09 (1H, d, J = 5.9 Hz), 8.49 (1H, s).

[Example 19]

6-(Difluoromethoxy)-5-((2-(4-((4-hydroxypiperidin-1-yl)methyl)benzamide)pyridin-4-yl)oxy)-N- Methyl-1H-indole-1-carboxamide

[chemical formula 98]

Under a nitrogen atmosphere at room temperature, triethylamine (17 μL, 0.123 mmol) and commercially available 4-(chloromethyl)benzoyl chloride (11.5 mg, 0.061 mmol) were added to that described in Production Example 19-7 5-((2-aminopyridin-4-yl)oxy)-6-(difluoromethoxy)-N-methyl-1H-indole-1-carboxamide (4.3mg, 0.012mmol) and in a mixture of tetrahydrofuran (0.5 mL). The mixture was stirred at room temperature for 2.5 hours, and water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with saturated saline solution, and then dried over anhydrous sodium sulfate, and the resultant was filtered with NH silica gel (ethyl acetate) and concentrated under vacuum to obtain a crude product (6.18 mg) .

The crude product (6.18 mg) was dissolved in N,N-dimethylformamide (0.5 mL), and commercially available 4-hydroxypiperidine (17.7 mg, 0.175 mmol) was added at room temperature under nitrogen atmosphere, And the mixture was stirred for 14 hours. To the reaction mixture were added water and ethyl acetate for fractionation, and the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by NH silica gel TLC (ethyl acetate) to obtain the title compound (6.0 mg, 86%). ¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.50-1.66 (2H, m), 1.83-1.94 (2H, m), 2.16 (2H, t, J=9.7Hz), 2.67-2.78 (2H, m), 3.08(3H, d, J=4.4Hz), 3.54(2H, s), 3.62-3.77(2H, m), 5.46-5.57(1H, m), 6.53(1H, t, J=73.9Hz ), 6.61 (1H, d, J = 3.7Hz), 6.64 (1H, dd, J = 5.7, 2.4Hz), 7.38-7.46 (4H, m), 7.80 (2H, d, J = 8.1Hz), 7.91 (1H,d,J=2.2Hz), 8.15(1H,d,J=5.9Hz), 8.24(1H,s), 8.53(1H,brs).

The starting material 5-((2-aminopyridin-4-yl)oxy)-6-(difluoromethoxy)-N-methyl-1H-indole-1-carboxamide was synthesized by the following method.

[Production Example 19-1]

4-(Difluoromethoxy)-3-hydroxybenzaldehyde

[chemical formula 99]

Dissolve commercially available 3,4-dihydroxybenzaldehyde (5 g, 36.2 mmol) and commercially available sodium chlorodifluoroacetate (5.57 g, 36.5 mmol) in N,N-dimethylformamide (45 mL) and water (905 μL), and then sodium hydroxide (1.48 g, 37.0 mmol) was added at room temperature, and the mixture was heated and stirred at 120° C. for 2 hours. The solvent was evaporated under vacuum, the residue was cooled to 0°C, and 5M hydrochloric acid and diethyl ether were added for fractionation. The organic layer was washed with water and a saturated saline solution, and then the solvent was evaporated. The residue was dissolved in dichloromethane, the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-7:3), and then the target fraction was concentrated in vacuo to obtain the The title compound (2.66 g, 39%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.69-5.74 (1H, m), 6.65 (1H, t, J=72.5Hz), 7.23-7.31 (1H, m), 7.46 (1H, dd, J = 8.4, 1.8 Hz), 7.54 (1H, d, J = 1.8 Hz), 9.92 (1H, s).

[Production Example 19-2]

3-(Benzyloxy)-4-(difluoromethoxy)benzaldehyde

[chemical formula 100]

Potassium carbonate (3.91 g, 28.3 mmol) and benzyl bromide (2.5 mL, 21.1 mmol) were added to 4-(difluoromethoxy)-3-hydroxybenzene described in Production Example 19-1 at room temperature Formaldehyde (2.66 g, 14.2 mmol) was dissolved in acetonitrile (50 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and then the solvent was evaporated. The resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2). The target fractions were concentrated under vacuum and the title compound was then obtained quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.21 (2H, s), 6.68 (1H, t, J = 74.3Hz), 7.31-7.51 (7H, m), 7.57 (1H, d, J = 1.8Hz), 9.92 (1H, s).

[Production example 19-3]

(E)-2-(Benzyloxy)-1-(difluoromethoxy)-4-(2-nitrovinyl)benzene

[chemical formula 101]

3-(Benzyloxy)-4-(difluoromethoxy)benzaldehyde (3.94 g, 14.2 mmol) described in Production Example 19-2 was dissolved in acetic acid (11 mL), and then at room temperature under nitrogen Ammonium acetate (1.27 g, 16.4 mmol) and nitromethane (1.9 mL, 35.1 mmol) were added under atmosphere, and the mixture was heated and stirred at 130° C. for 2 hr. The mixture was cooled to room temperature and then heated and stirred at 130 °C for a further 1 hour. The precipitate was collected by filtration and washed with a liquid mixture of acetic acid and ethanol to obtain the title compound (2.36 g, 52%). The filtrate was dissolved in dichloromethane, the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1-4:1), and then the target fraction was concentrated in vacuo. The precipitate was washed with ethanol to obtain the title compound (406 mg, 8.9%). ¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.18 (2H, s), 6.65 (1H, t, J=74.3Hz), 7.12-7.19 (2H, m), 7.21-7.29 (1H, m) , 7.32-7.45 (5H, m), 7.48 (1H, d, J = 13.9Hz), 7.92 (1H, d, J = 13.9Hz).

[Production example 19-4]

5-(Benzyloxy)-6-(difluoromethoxy)-1H-indole

[chemical formula 102]

At room temperature, fuming nitric acid (6.0 mL, 133 mmol) was slowly added to (E)-2-(benzyloxy)-3-(difluoromethoxy)-4-( 2-Nitrovinyl)benzene (2.77 g, 8.61 mmol) and acetic acid (36 mL) were in a mixture in an ice bath, and the mixture was stirred for 7.5 hours. A portion of the reaction mixture was heated and stirred at 50°C for 30 minutes, then at 70°C for 40 minutes, and then at 75°C for 165 minutes. A portion of the reaction mixture was poured onto ice and the resultant was diluted with ethyl acetate for fractionation. The organic layer was washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=17:3-3:1), then the target fraction was concentrated in vacuo, and then The residue was collected by filtration and washed with diethyl ether to obtain a crude product (23.6 mg). The remaining reaction mixture was heated and stirred at 65 °C for 3 hours, then the resultant was poured onto ice, and the precipitate was then collected by filtration and washed with a liquid mixture of acetic acid and ethanol to obtain a crude product B (603 mg). Ethyl acetate was added to the filtrate for fractionation. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was evaporated. The residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:1), then the target fraction was concentrated in vacuo, and the residue was Diethyl ether was added to the mixture, and the precipitate was collected by filtration to obtain a crude product C (73.3 mg).

Crude products A, B, and C (550 mg) were suspended in ethanol (5.5 mL), acetic acid (5.5 mL), and water (676 μL), then iron powder (419 mg, 7.51 mmol) was added under a nitrogen atmosphere, and the The mixture was heated and stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, and ethyl acetate and an aqueous sodium disulfite solution were added for fractionation. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and filtered, and then the solvent was evaporated. The residue was dissolved in dichloromethane, the resultant was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2), and then the target fraction was concentrated in vacuo to obtain The title compound (245 mg, 13%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.15 (2H, s), 6.45-6.49 (1H, m), 6.58 (1H, t, J=76.0Hz), 7.19-7.22 (1H, m) , 7.23 (1H, s), 7.24-7.27 (1H, m), 7.29-7.43 (3H, m), 7.44-7.50 (2H, m), 8.12 (1H, brs).

[Production Example 19-5]

6-(Difluoromethoxy)-1H-indol-5-ol

[chemical formula 103]

5-(Benzyloxy)-6-(difluoromethoxy)-1H-indole (245 mg, 0.847 mmol) described in Production Example 19-4 was dissolved in ethanol (8.0 mL), and then 10% palladium-carbon (water content, 50%) (90 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere for 75 minutes. The reaction mixture was diluted with ethyl acetate and the catalyst was filtered off through celite. The filtrate was concentrated under vacuum and then filtered through silica gel (ethyl acetate). The title fractions were concentrated under vacuum to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.15 (1H, s), 6.41-6.49 (1H, m), 6.53 (1H, t, J=74.1Hz), 7.15-7.24 (3H, m) , 8.06 (1H, brs).

[Production example 19-6]

4-((6-(Difluoromethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 104]

Under a nitrogen atmosphere, 6-(difluoromethoxy)-1H-indol-5-ol (35.1 mg, 0.176 mmol) described in Production Example 19-5, N-(4-Chloropyridin-2-yl)acetamide (89.0 mg, 0.522 mmol), and potassium tert-butoxide (44.0 mg, 0.392 mmol) were dissolved in dimethylsulfoxide (500 μL), and the mixture was heated and stirred at 160° C. for 80 minutes. The reaction liquid was cooled to room temperature, and water and ethyl acetate were added for segmentation. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then filtered, and then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-9:1 ) was purified, then the target fraction was concentrated in vacuo to obtain a crude product (12.5 mg).

The crude product (12.5 mg) was dissolved in methanol (500 μL), 28% sodium methoxide (39 μL, 0.382 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was heated and stirred at 65° C. for 1 hr. The mixture was cooled to room temperature, 28% sodium methoxide (39 μL, 0.382 mmol) was added, and the mixture was heated and stirred at 65° C. for 2.5 hrs. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the resultant was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=97:3-9:1 ) was purified, and then the target fraction was concentrated under vacuum to obtain the title compound (4.4 mg, 8.6%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.48 (2H, brs), 5.91 (1H, d, J=1.8Hz), 6.28 (1H, dd, J=5.9, 1.8Hz), 6.45 (1H , t, J=74.5Hz), 6.52-6.58(1H, m), 7.30(1H, t, J=2.9Hz), 7.36(1H, s), 7.41(1H, s), 7.90(1H, d, J = 5.9 Hz), 8.35 (1H, brs).

[Production example 19-7]

5-((2-aminopyridin-4-yl)oxy)-6-(difluoromethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 105]

4-((6-(Difluoromethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine (4.4 mg, 0.015 mmol) described in Production Example 19-6 was dissolved in N,N-Dimethylformamide (500 μL), then 50%-72% oily sodium hydride (4.1 mg) was added at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0°C again, and methyl phenylcarbamate (16.4 mg, 0.108 mmol) described in Production Example 1-7 was added, and the mixture was stirred at room temperature for 50 minutes. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with saturated saline solution, then dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-9:1 ) was purified, and then the target fraction was concentrated under vacuum to obtain the title compound (4.3 mg, 82%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.08 (3H, d, J = 4.8Hz), 4.44 (2H, brs), 5.49 (1H, brs), 5.91 (1H, d, J = 1.8Hz ), 6.26(1H, dd, J=6.2, 2.2Hz), 6.50(1H, t, J=74.0Hz), 6.61(1H, d, J=3.7Hz), 7.35(1H, s), 7.41(1H , d, J=3.7Hz), 7.92 (1H, d, J=5.9Hz), 8.23 (1H, s).

[Example 20]

6-(2-methoxyethoxy)-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H -Indole-1-carboxamide

[chemical formula 106]

Benzotriazole (609 mg, 5.11 mmol) was dissolved in dichloromethane (25 mL), thionyl chloride (373 μL, 5.11 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (1.3 g, 4.26 mmol) described in Production Example 1-12 at room temperature, and The mixture was stirred for 30 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate and the anhydrous sodium sulfate was washed with dichloromethane, and the filtrate was added to the product in Production Example 20-7 at 0° C. over 5 minutes. The 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide (0.95g , 2.67mmol), triethylamine (1.86mL, 13.3mmol), and 4-dimethylaminopyridine (16mg, 0.133mmol) in N, N-dimethylformamide (3mL) and dichloromethane (20mL) and the mixture was rinsed with dichloromethane (10 mL), and then stirred at the same temperature for 5 minutes. The mixture was stirred at room temperature for 2 hours, then 40% aqueous methylamine (2.3 mL, 26.7 mmol) was added, and then the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate for fractionation, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated in vacuo, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=49: 1-23:2) to obtain a crude product (1.11 g).

The crude product (1.11 g) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (5.0 mL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes, then the resultant was concentrated under vacuum, and then the residue was dissolved in dichloromethane and triethylamine, and the resultant was concentrated under vacuum. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-22:3) to obtain the title compound (829 mg, 57%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 1.59-1.69 (2H, m), 1.83 (2H, d, J=14.1Hz), 2.68 (1H, tt, J=12.0, 3.6Hz) , 2.75(2H, td, J=12.2, 2.4Hz), 3.04(3H, d, J=4.9Hz), 3.17-3.23(2H, m), 3.26(3H, s), 3.55-3.61(2H, m ), 4.15-4.21 (2H, m), 5.57-5.65 (1H, m), 6.53 (1H, d, J=3.4Hz), 6.62 (1H, dd, J=5.8, 2.4Hz), 7.25 (1H, d, J=3.9Hz), 7.30-7.34(3H, m), 7.77-7.82(2H, m), 7.91(1H, d, J=2.4Hz), 8.02(1H, s), 8.10(1H, d , J=5.9Hz), 8.50 (1H, brs).

The starting material 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-methanol was synthesized by amides.

[Production Example 20-1]

3-Hydroxy-4-(2-methoxyethoxy)benzaldehyde

[chemical formula 107]

Commercially available 3,4-dihydroxybenzaldehyde (39.3 g, 285 mmol) and sodium carbonate (45.2 g, 427 mmol) were dissolved in N,N-dimethylformamide (400 mL), and then heated at room temperature under nitrogen Commercially available 2-bromoethylmethyl ether (26.7 mL, 285 mmol) was added under atmosphere, and the mixture was stirred for 5 days. The mixture was cooled to 0°C, and then 2M hydrochloric acid, ethyl acetate and water were added for fractionation. The aqueous layer was extracted with ethyl acetate, and then the combined organic layers were washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated, dichloromethane was added, the precipitate was separated by filtration, and then the resulting filtrate was purified by silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1). The target fractions were concentrated in vacuo to obtain the title compound (12.9 g, 23%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.47 (3H, s), 3.76-3.80 (2H, m), 4.25-4.29 (2H, m), 6.40 (1H, brs), 7.01 (1H, d, J = 8.4 Hz), 7.41 (1H, dd, J = 8.2, 2.0 Hz), 7.45 (1H, d, J = 1.8 Hz), 9.85 (1H, s).

[Production example 20-2]

3-(Benzyloxy)-4-(2-methoxyethoxy)benzaldehyde

[chemical formula 108]

Potassium carbonate (11.8 g, 85.7 mmol) and benzyl chloride (10 mL, 86.9 mmol) were added to 3-hydroxy-4-(2-methoxy (ethoxy)benzaldehyde (12.9 g, 65.9 mmol) in a liquid mixture in ethanol (130 mL), and the mixture was heated and stirred at 90° C. for 2 hours. The mixture was cooled to 0°C, and then 2M hydrochloric acid, ethyl acetate and water were added for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1). The target fractions were concentrated in vacuo to obtain the title compound (17.6 g, 93%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.46 (3H, s), 3.79-3.85 (2H, m), 4.24-4.30 (2H, m), 5.18 (2H, s), 7.03 (1H, d, J = 8.1 Hz), 7.29-7.35 (1H, m), 7.35-7.41 (2H, m), 7.43-7.50 (4H, m), 9.82 (1H, s).

[Production Example 20-3]

(E)-2-(Benzyloxy)-1-(2-methoxyethoxy)-4-(2-nitrovinyl)benzene

[chemical formula 109]

3-(Benzyloxy)-4-(2-methoxyethoxy)benzaldehyde (17.6 g, 61.5 mmol) described in Production Example 20-2 was dissolved in acetic acid (49.3 mL), and then dissolved in Ammonium acetate (5.69 g, 73.8 mmol) and nitromethane (8.32 mL, 154 mmol) were added at room temperature under nitrogen atmosphere, and the mixture was heated and stirred at 130° C. for 2 hrs. The mixture was cooled to room temperature, and then the precipitate was collected by filtration and washed with ethanol to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.46 (3H, s), 3.78-3.84 (2H, m), 4.21-4.27 (2H, m), 5.16 (2H, s), 6.97 (1H, d, J = 8.4Hz), 7.06 (1H, d, J = 1.8Hz), 7.16 (1H, dd, J = 8.4, 2.2Hz), 7.30-7.48 (6H, m), 7.91 (1H, d, J = 13.5Hz).

[Production example 20-4]

6-(2-Methoxyethoxy)-1H-indol-5-ol

[chemical formula 110]

At 25°C, 69% nitric acid (15 mL, 233 mmol) was added to (E)-2-(benzyloxy)-1-(2-methoxyethoxy)-4 described in Production Example 20-3 -(2-nitrovinyl)benzene (20.2 g, 61.5 mmol) and acetic acid (120 mL) in a mixture, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured onto ice, and the precipitate was collected by filtration and then washed with water to obtain a crude product (23.0 g).

The crude product (23.0 g) was suspended in methanol (500 mL), then 10% palladium-carbon (water content, 50%) (8 g) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 6 hr. The catalyst was filtered off with celite, the filtrate was concentrated in vacuo, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1-1:1). The target fractions were concentrated under vacuum to obtain the title compound (3.94 g, 31%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.48 (3H, s), 3.69-3.78 (2H, m), 4.16-4.23 (2H, m), 6.24 (1H, s), 6.41 (1H, ddd, J = 3.1, 2.1, 0.8 Hz), 6.97 (1H, s), 7.10 (1H, dd, J = 3.2, 2.5 Hz), 7.15 (1H, s), 7.94 (1H, brs).

[Production Example 20-5]

N-(4-((6-(2-methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide

[chemical formula 111]

6-(2-Methoxyethoxy)-1H-indol-5-ol (3.94 g, 19.0 mmol) described in Production Example 20-4 and N- (4-Chloropyridin-2-yl)acetamide (3.25 g, 19.0 mmol) was dissolved in dimethyl sulfoxide (25 mL), then 97% potassium tert-butoxide (2.20 g, 19.0 mmol) was added at room temperature, and The mixture was heated and stirred at 150°C for 13 hours. To the reaction liquid were added water and ethyl acetate at room temperature for fractionation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under vacuum, and then the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1-ethyl acetate:methanol= 49:1-9:1) for purification. The target fractions were concentrated under vacuum to obtain the title compound (3.45 g, 53%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 2.13 (3H, s), 3.27 (3H, s), 3.54-3.58 (2H, m), 4.07-4.11 (2H, m), 6.46- 6.50(1H, m), 6.54(1H, dd, J=5.8, 1.9Hz), 7.05(1H, s), 7.14-7.17(1H, m), 7.36(1H, s), 7.75(1H, brs) , 8.02 (1H, d, J=5.8Hz), 8.10 (1H, brs), 8.19 (1H, brs).

[Production example 20-6]

4-((6-(2-methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 112]

N-(4-((6-(2-methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide described in Example 20-5 will be produced (3.45 g, 10.1 mmol) was dissolved in methanol (50 mL), 2M sodium hydroxide solution (50 mL) was added at room temperature, and the mixture was heated and stirred at 70° C. for 3 hr. Water and ethyl acetate were added to the reaction mixture for fractionation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under vacuum, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=49 :1-24:1) for purification. The target fraction and the mixed fraction were respectively concentrated under vacuum, the mixed fraction was purified again by silica gel column chromatography (ethyl acetate:methanol=1:0-9:1), and then the resultant was combined with the above-mentioned target fraction Combination was performed to obtain the title compound (2.60 g, 86%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 3.31 (3H, s), 3.58-3.63 (2H, m), 4.08-4.11 (2H, m), 4.28 (2H, brs), 5.90 ( 1H, d, J=2.4HZ), 6.29(1H, dd, J=6.1, 2.2Hz), 6.44-6.52(1H, m), 7.06(1H, s), 7.15-7.20(1H, m), 7.34 (1H, s), 7.88 (1H, d, J=5.8Hz), 8.22 (1H, brs).

[Production example 20-7]

5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 113]

4-((6-(2-methoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine (2.60 g, 8.67 mmol) described in Production Example 20-6 ) was dissolved in N,N-dimethylformamide (50 mL), then 50%-72% oily sodium hydride (499 mg) was added at room temperature under nitrogen atmosphere. Methyl phenylcarbamate (1.97 g, 13.0 mmol) described in Production Example 1-7 was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C and ethyl acetate and water were added for partitioning. The aqueous layer was extracted twice with ethyl acetate, sodium chloride water was added to the aqueous layer, and the resultant was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under vacuum, and then the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate:methanol= 49:1-24:1) for purification. The target fractions were concentrated under vacuum and ethyl acetate was added, and the precipitate was collected by filtration and washed to obtain the title compound (2.23 g, 72%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 3.06 (3H, d, J=4.9Hz), 3.29 (3H, s), 3.59-3.63 (2H, m), 4.14-4.17 (2H, m), 4.30(2H, brs), 5.52-5.59(1H, m), 5.89(1H, d, J=2.4Hz), 6.27(1H, dd, J=5.8, 1.9Hz), 6.55(1H, d , J=3.9Hz), 7.27-7.29 (2H, m), 7.89 (1H, d, J=5.9Hz), 7.99 (1H, s).

[Example 21]

6-(2-methoxyethoxy)-N-methyl-5-((2-(4-(1-methylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy base)-1H-indole-1-carboxamide

[chemical formula 114]

35% aqueous formaldehyde (186 μL, 2.36 mmol) and sodium triacetoxyborohydride (200 mg, 0.946 mmol) were added to 6-(2-methoxyethoxy)-N -Methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (257mg, 0.473mmol) and tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 3 minutes. To the reaction mixture was added acetic acid (54 μL, 0.946 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-23:2). The title fractions were concentrated under vacuum to obtain the title compound quantitatively.

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δ (ppm): 1.75-1.88 (4H, m), 2.02-2.11 (2H, m), 2.33 (3H, s), 2.49-2.59 (1H, m), 2.99(2H, d, J=11.2Hz), 3.05(3H, d, J=4.9Hz), 3.26(3H, s), 3.56-3.60(2H, m), 4.15-4.21(2H, m), 5.52 -5.58(1H, m), 6.54(1H, d, J=3.9Hz), 6.61(1H, dd, J=5.8, 2.4Hz), 7.25-7.27(1H, m), 7.30-7.34(3H, m ), 7.79 (2H, d, J = 8.3Hz), 7.91 (1H, d, J = 2.4Hz), 8.01 (1H, s), 8.09 (1H, d, J = 5.8Hz), 8.48 (1H, brs ).

[Example 22]

5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy base) -N-methyl-1H-indole-1-carboxamide

[chemical formula 115]

Sodium triacetoxyborohydride (286 mg, 1.35 mmol) and commercially available 2-glycolaldehyde (86.1 mg, 1.43 mmol) were added to 6-(2-methoxy Ethoxy)-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (250 mg, 0.46 mmol) and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 3 hours and 45 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The solvent was evaporated, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-97:3-9:1). The target fraction was concentrated under vacuum, and then the precipitate was collected by filtration and washed with a liquid mixture of diethyl ether and n-hexane to obtain the title compound (236 mg, 87%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.70-1.92 (4H, m), 2.14-2.25 (2H, m), 2.53-2.64 (3H, m), 3.01-3.08 (5H, m), 3.26(3H, s), 3.56-3.60(2H, m), 3.63(2H, t, J=5.4Hz), 4.15-4.20(2H, m), 5.50-5.59(1H, m), 6.54(1H, d, J = 3.7Hz), 6.61 (1H, dd, J = 5.7, 2.4Hz), 7.24-7.28 (1H, m), 7.30-7.35 (3H, m), 7.80 (2H, d, J = 8.4Hz ), 7.91 (1H, d, J=2.2Hz), 8.01 (1H, s), 8.09 (1H, d, J=5.9Hz), 8.50 (1H, brs).

[Example 23]

5-((2-(4-(1-isopropylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N -Methyl-1H-indole-1-carboxamide

[chemical formula 116]

Acetone (54 μL, 0.736 mmol), sodium triacetoxyborohydride (62.4 mg, 0.294 mmol), and acetic acid (17 μL, 0.294 mmol) were added to 6-(2-methoxy Ethoxy)-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-methyl A solution of the amide (20 mg, 0.037 mmol) in tetrahydrofuran (3 mL). The reaction liquid was stirred overnight at the same temperature. To the reaction liquid were added saturated aqueous sodium bicarbonate solution and ethyl acetate for fractionation at room temperature. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The desiccant was separated by filtration and the resultant was then concentrated under vacuum. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (6.6 mg, 31%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.99 (6H, d, J=6.6Hz), 1.54-1.68 (2H, m), 1.70-1.81 (2H, m), 2.16-2.26 ( 2H, m), 2.44-2.57 (1H, m), 2.66-2.76 (1H, m), 2.82-2.91 (5H, m), 3.12 (3H, s), 3.45-3.52 (2H, m), 4.05- 4.13(2H, m), 6.63(1H, d, J=3.7Hz), 6.67(1H, dd, J=5.7, 2.4Hz), 7.33(2H, d, J=8.4Hz), 7.45(1H, s ), 7.69 (1H, d, J = 2.6Hz), 7.78 (1H, d, J = 4.0Hz), 7.89 (2H, d, J = 8.4Hz), 8.08 (1H, s), 8.14-8.21 (2H , m), 10.64 (1H, s).

[Example 24]

6-(2-Ethoxyethoxy)-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H -Indole-1-carboxamide

[chemical formula 117]

Trifluoroacetic acid (1.79 mL, 23.2 mmol) was added to 4-(4-((4-((6-(2-ethoxyethoxy)-1 -(Methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (382 mg, 0.581 mmol) in solution in dichloromethane (10 mL). The reaction liquid was stirred at the same temperature for 1 hour. The reaction liquid was concentrated under vacuum, and trifluoroacetic acid was removed. The residue was diluted with dichloromethane, and then triethylamine was added to neutralize the trifluoroacetic acid. The solution was concentrated under vacuum and then the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=49:1-17:3) to obtain the title compound (276 mg, 85%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.94 (3H, t, J=7.0Hz), 1.44-1.57 (2H, m), 1.63-1.72 (2H, m), 2.47-2.69 ( 3H, m), 2.85(3H, d, J=4.4Hz), 2.97-3.05(2H, m), 3.29(2H, q, J=7.0Hz), 3.47-3.58(2H, m), 4.04-4.13 (2H, m), 6.57-6.73 (2H, m), 7.31 (2H, d, J=8.1Hz), 7.45 (1H, s), 7.70 (1H, d, J=2.2Hz), 7.78 (1H, d, J = 3.7 Hz), 7.90 (2H, d, J = 8.8 Hz), 8.08 (1H, s), 8.13-8.24 (2H, m), 10.64 (1H, s).

The starting material 4-(4-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)) was synthesized by oxy)pyridin-2-yl)carbamoyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester.

[Production Example 24-1]

4-(2-Ethoxyethoxy)-3-hydroxybenzaldehyde

[chemical formula 118]

Commercially available 2-bromoethyl ether (33.8 g, 221 mmol) was added to commercially available 3,4-dihydroxybenzaldehyde (30.5 g, 221 mmol) and sodium carbonate (35.1 g) at room temperature under nitrogen atmosphere , 331 mmol) in N,N-dimethylformamide (310 mL). The liquid mixture was stirred at room temperature for 5 days. The reaction liquid was cooled to 0°C, and diluted with 2M hydrochloric acid, ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The insoluble material was separated by filtration with dichloromethane, and the starting material was removed. The filtrate was purified by silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1) to obtain the title compound (13.2 g, 28%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.27 (3H, t, J=7.0Hz), 3.63 (2H, q, J=7.0Hz), 3.80-3.85 (2H, m), 4.24-4.30 (2H, m), 6.65(1H, s), 7.02(1H, d, J=8.4Hz), 7.38-7.42(1H, m), 7.45(1H, d, J=2.2Hz), 9.85(1H, s).

[Production Example 24-2]

3-(Benzyloxy)-4-(2-ethoxyethoxy)benzaldehyde

[chemical formula 119]

Potassium carbonate (11.3 g, 81.5 mmol) and benzyl chloride (9.5 mL, 82.6 mmol) were added to 4-(2-ethoxyethoxy in a solution of -3-hydroxybenzaldehyde (13.2 g, 62.7 mmol) in ethanol (130 mL). The liquid mixture was stirred under heat at 90°C for 2 hours. The reaction liquid was cooled to 0°C, and then diluted with 2M hydrochloric acid, ethyl acetate and water. The organic layer was washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The resulting residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (13.5 g, 72% ).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.22 (3H, t, J=7.0Hz), 3.63 (2H, q, J=7.0Hz), 3.82-3.90 (2H, m), 4.23-4.30 (2H, m), 5.18 (2H, s), 7.03 (1H, d, J=7.7Hz), 7.28-7.34 (1H, m), 7.35-7.42 (2H, m), 7.43-7.50 (4H, m ), 9.82 (1H, s).

[Production example 24-3]

(E)-2-(Benzyloxy)-1-(2-ethoxyethoxy)-4-(2-nitrovinyl)benzene

[chemical formula 120]

Ammonium acetate (4.16 g, 53.9 mmol) and nitromethane (6.1 mL, 113 mmol) were added to 3-(benzyloxy)-4-( A solution of 2-ethoxyethoxy)benzaldehyde (13.5 g, 45.0 mmol) in acetic acid (36 mL). The liquid mixture was heated and stirred at reflux for 2 hours at 130°C. The reaction liquid was allowed to stand to cool to room temperature. The precipitate was collected by filtration and washed with ethanol to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.22 (3H, t, J=7.1Hz), 3.62 (2H, q, J=7.0Hz), 3.82-3.88 (2H, m), 4.21-4.26 (2H, m), 5.16 (2H, s), 6.97 (1H, d, J=8.3Hz), 7.06 (1H, d, J=2.2Hz), 7.16 (1H, dd, J=8.3, 2.1Hz) , 7.29-7.50 (6H, m), 7.91 (1H, d, J=13.6Hz).

[Production example 24-4]

(E)-1-(Benzyloxy)-2-(2-ethoxyethoxy)-4-nitro-5-(2-nitrovinyl)benzene

[chemical formula 121]

At 25°C, nitric acid (11 mL, 69%, 171 mmol) was added to (E)-2-(benzyloxy)-1-(2-ethoxyethoxy)- 4-(2-Nitrovinyl)benzene (15.4 g, 44.9 mmol) and acetic acid (100 mL), and the mixture was stirred for 6 hours. The reaction liquid was poured onto ice. The suspension was subjected to suction filtration, and the product was washed with water to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.23 (3H, t, J=7.0Hz), 3.62 (2H, q, J=6.9Hz), 3.84-3.90 (2H, m), 4.29-4.34 (2H, m), 5.27 (2H, s), 6.93 (1H, s), 7.23 (1H, d, J=13.6Hz), 7.35-7.50 (5H, m), 7.84 (1H, s), 8.57 ( 1H, d, J = 13.5 Hz).

[Production Example 24-5] 6-(2-ethoxyethoxy)-1H-indol-5-ol

[chemical formula 122]

At room temperature, 10% palladium-carbon (water content, 50%) (6 g) was added to (E)-1-(benzyloxy)-2-(2-ethoxyl) described in Production Example 24-4 Ethoxy)-4-nitro-5-(2-nitrovinyl)benzene (17.5 g, 44.9 mmol) in methanol (180 mL). The reaction liquid was stirred at room temperature under a hydrogen atmosphere. After 6 hours, the catalyst was filtered off through celite. The filtrate was concentrated under vacuum, and then the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1-1:1) to obtain the title compound (3.28 g, 33% ).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.29 (3H, t, J = 7.0Hz), 3.63 (2H, q, J = 7.0Hz), 3.73-3.80 (2H, m), 4.16-4.24 (2H, m), 6.41 (1H, td, J = 2.1, 1.1Hz), 6.46 (1H, s), 6.99 (1H, s), 7.10 (1H, dd, J = 3.1, 2.4Hz), 7.15 ( 1H, s), 7.93 (1H, brs).

[Production example 24-6]

N-(4-((6-(2-ethoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide

[chemical formula 123]

Dimethylsulfoxide (20 mL) was added to 6-(2-ethoxyethoxy)-1H-indol-5-ol (3.28 g, 14.8mmol), N-(4-chloropyridin-2-yl)acetamide (2.78g, 16.3mmol) described in Production Example 1-5, and potassium tert-butoxide (1.83g, 16.3mmol) in the mixture. The liquid mixture was stirred overnight at 150°C. The reaction liquid was allowed to stand to cool to room temperature, and then diluted with water and ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate, and then the desiccant was separated by filtration. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-19:1) to obtain the title compound (2.5 g , 48%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.09 (3H, t, J = 7.0Hz), 2.14 (3H, s), 3.41 (2H, q, J = 7.0Hz), 3.56-3.66 (2H , m), 4.05-4.13 (2H, m), 6.44-6.50 (1H, m), 6.53 (1H, dd, J=5.9, 2.6Hz), 7.05 (1H, d, J=0.7Hz), 7.16 ( 1H, dd, J=3.3, 2.6Hz), 7.36(1H, s), 7.75(1H, brs), 8.01(1H, d, J=5.9Hz), 8.11(1H, brs), 8.19(1H, brs ).

[Production example 24-7]

4-((6-(2-ethoxyethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 124]

2M sodium hydroxide solution (20 mL) was added to N-(4-((6-(2-ethoxyethoxy)-1H-indole) described in Production Example 24-6 at room temperature under nitrogen atmosphere Indol-5-yl)oxy)pyridin-2-yl)acetamide (2.5 g, 7.04 mmol) was dissolved in methanol (20 mL), and the mixture was heated and stirred at 75° C. under reflux for 2 hrs. The reaction liquid was allowed to stand to cool to room temperature, and then diluted with ethyl acetate and water. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:9-0:1-ethyl acetate:methanol=49:1-24:1) to obtain the title compound (1.92 g , 87%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.12 (3H, t, J=7.0Hz), 3.45 (2H, q, J=7.2Hz), 3.60-3.72 (2H, m), 4.03-4.13 (2H, m), 4.29 (2H, s), 5.89 (1H, d, J=1.8Hz), 6.29 (1H, dd, J=6.2, 2.2Hz), 6.44-6.54 (1H, m), 7.05 ( 1H, s), 7.18 (1H, dd, J = 3.1, 2.4 Hz), 7.34 (1H, s), 7.88 (1H, d, J = 5.9 Hz), 8.25 (1H, brs).

[Production example 24-8]

5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 125]

50%-72% oily sodium hydride (265 mg) was added to 4-((6-(2-ethoxyethoxy)-1H -Indol-5-yl)oxy)pyridin-2-amine (1.92 g, 6.13 mmol) in solution in N,N-dimethylformamide (20 mL). The reaction liquid was stirred at the same temperature for 10 minutes. To the reaction liquid was added methyl phenylcarbamate (1.20 g, 7.97 mmol) described in Production Example 1-7, and then the mixture was warmed up to room temperature and stirred for 1 hour. Water and ethyl acetate were added to the reaction liquid. The organic layer was washed successively with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by NH silica gel column chromatography (solution: n-heptane: ethyl acetate = 9:1-0:1) to obtain the title compound (1.97 g, 87%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.01 (3H, t, J = 7.0Hz), 2.84 (3H, d, J = 4.4Hz), 3.37 (2H, q, J = 7.1Hz ), 3.54-3.59 (2H, m), 4.02-4.10 (2H, m), 5.69 (1H, d, J = 2.2Hz), 5.77 (2H, s), 6.09 (1H, dd, J = 5.9, 2.2 Hz), 6.60 (1H, d, J=3.3Hz), 7.35 (1H, s), 7.71-7.77 (2H, m), 8.04 (1H, s), 8.09-8.17 (1H, m).

[Production example 24-9]

4-(4-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine-2- Base) carbamoyl) phenyl) piperidine-1-carboxylic acid tert-butyl ester

[chemical formula 126]

Thionyl chloride (370 μL, 5.06 mmol) was added to a solution of benzotriazole (603 mg, 5.06 mmol) in dichloromethane (20 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 minutes, and then 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (1.03 g, 3.38 mmol) described in Production Example 1-12 was added ), and the mixture was stirred for 1 hour. The reaction liquid was filtered through anhydrous sodium sulfate on a glass filter, and the anhydrous sodium sulfate was washed with dichloromethane. Under a nitrogen atmosphere at 0° C., triethylamine (1.87 mL, 13.5 mmol), 4-dimethylaminopyridine (16.5 mg, 0.135 mmol), and a 5 -((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide (500mg, 1.35mmol) in A solution in tetrahydrofuran (5 mL) was continuously added to the resulting filtrate, and the mixture was stirred at room temperature for 4 hrs. To the reaction liquid, an excess amount of methylamine was added, and then the resultant was diluted with ethyl acetate and water for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate, and the desiccant was separated by filtration. The filtrate was concentrated under vacuum. The resulting residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1) to obtain the title compound (383 mg, 43%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.94 (3H, t, J=7.1Hz), 1.42 (9H, s), 1.43-1.60 (2H, m), 1.69-1.84 (2H, m), 2.75(3H, brs), 2.85(3H, d, J=4.4Hz), 3.29(2H, q, J=7.0Hz), 3.47-3.58(2H, m), 3.98-4.16(4H, m ), 6.56-6.71 (2H, m), 7.34 (2H, d, J = 8.4Hz), 7.45 (1H, s), 7.70 (1H, d, J = 2.6Hz), 7.78 (1H, d, J = 3.7Hz), 7.90 (2H, d, J = 8.4Hz), 8.08 (1H, s), 8.12-8.24 (2H, m), 10.66 (1H, s).

[Example 25]

6-(2-Ethoxyethoxy)-5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy base) -N-methyl-1H-indole-1-carboxamide

[chemical formula 127]

Commercially available 2-glycolaldehyde (48.5 mg, 0.807 mmol), sodium triacetoxyborohydride (91 mg, 0.43 mmol), and acetic acid (25 μL, 0.43 mmol) were added to the mixture described in Example 24 at room temperature. 6-(2-ethoxyethoxy)-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)- 1H-Indole-1-carboxamide (30 mg, 0.054 mmol) in suspension in THF (3 mL). The reaction liquid was stirred at room temperature for 2 hours. To the reaction liquid was added saturated aqueous sodium bicarbonate solution at room temperature, and the mixture was diluted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was concentrated under vacuum. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (20.1 mg, 62%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.07 (3H, t, J=7.0Hz), 1.67-1.99 (4H, m), 2.20 (2H, td, J=11.7, 2.6Hz), 2.53 -2.66(3H, m), 2.98-3.11(5H, m), 3.40(2H, q, J=7.0Hz), 3.59-3.69(4H, m), 4.16-4.20(2H, m), 5.02(1H , s), 5.69-5.80 (1H, m), 6.51 (1H, d, J=3.7Hz), 6.62 (1H, dd, J=5.7, 2.4Hz), 7.25 (1H, d, J=3.7Hz) , 7.28-7.36(3H, m), 7.76-7.83(2H, m), 7.91(1H, d, J=2.6Hz), 8.02(1H, s), 8.09(1H, d, J=5.9Hz), 8.62 (1H, s).

[Example 26]

6-(2-Ethoxyethoxy)-5-((2-(4-(1-ethylazetidin-3-yl)benzamide)pyridin-4-yl)oxy) -N-Methyl-1H-indole-1-carboxamide

[chemical formula 128]

Sodium triacetoxyborohydride (172 mg, 0.812 mmol) and acetaldehyde (51.2 mg, 1.16 mmol) were added to 5-((2-(4-(aza Cyclobutan-3-yl)benzamide)pyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide ( 215 mg, 0.406 mmol) and tetrahydrofuran (4.0 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1-ethyl acetate:methanol=99 :1-19:1) for purification. The target fractions were concentrated under vacuum, and the residue was collected by filtration and washed with diethyl ether to obtain the title compound (180 mg, 79%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.00 (3H, t, J = 7.1 Hz), 1.07 (3H, t, J = 7.0 Hz), 2.51 (2H, q, J = 7.1 Hz), 3.06(3H, d, J=4.8Hz), 3.09-3.16(2H, m), 3.40(2H, q, J=7.1Hz), 3.60-3.65(2H, m), 3.71-3.80(3H, m) , 4.15-4.20(2H, m), 5.47-5.57(1H, m), 6.54(1H, d, J=3.7Hz), 6.61(1H, dd, J=5.7, 2.4Hz), 7.24-7.27(1H , m), 7.34(1H, s), 7.36-7.40(2H, m), 7.77-7.83(2H, m), 7.91(1H, d, J=2.2Hz), 8.01(1H, s), 8.10( 1H, d, J = 5.9 Hz), 8.47 (1H, brs).

The starting material 5-((2-(4-(azetidin-3-yl)benzamide)pyridin-4-yl)oxy)-6-(2-ethoxyethyl) was synthesized by Oxy)-N-methyl-1H-indole-1-carboxamide.

[Production Example 26-1]

3-(4-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine-2- Base) carbamoyl) phenyl) azetidine-1-carboxylic acid tert-butyl ester

[chemical formula 129]

Benzotriazole (335 mg, 2.81 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (200 μL, 2.74 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzoic acid (650 mg, 2.34 mmol) described in Production Example 26-5 at room temperature , and the mixture was stirred for 25 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate, and then the anhydrous sodium sulfate was washed with dichloromethane, and then the filtrate was added to the 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide (300mg , 0.810 mmol), triethylamine (1.3 mL, 9.38 mmol), and 4-dimethylaminopyridine (9.9 mg, 0.081 mmol) in a mixture of tetrahydrofuran (16 mL). The mixture was stirred at room temperature for 3 hours, then water and ethyl acetate were added to the reaction mixture for segmentation, and the organic layer was washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, then the filtrate was concentrated in vacuo, the residue was dissolved in tetrahydrofuran, excess 9.8M methanolic methylamine was added at room temperature, and the mixture was stirred for 75 minutes. The reaction mixture was concentrated under vacuum, the residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:3-0:1 -ethyl acetate:methanol=9:1) for purification. The mixed fractions were concentrated under vacuum, the residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-1:3-0: 1-ethyl acetate:methanol=9:1) for purification. The title fractions were concentrated in vacuo to obtain the title compound (279 mg, 76%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.07 (3H, t, J = 7.0Hz), 1.47 (9H, s), 2.81 (3H, d, J = 4.8Hz), 3.40 (2H, q , J=6.8Hz), 3.60-3.65 (2H, m), 3.73-3.83 (1H, m), 3.93-4.01 (2H, m), 4.15-4.20 (2H, m), 4.35 (2H, t, J =8.6Hz), 5.44-5.54(1H, m), 6.56(1H, d, J=3.7Hz), 6.61(1H, dd, J=5.9, 1.8Hz), 7.23-7.29(1H, m), 7.34 (1H, s), 7.42 (2H, d, J = 8.4Hz), 7.85 (2H, d, J = 8.4Hz), 7.91 (1H, d, J = 2.2Hz), 8.01 (1H, s), 8.09 (1H, d, J = 5.9 Hz), 8.55 (1H, brs).

[Production Example 26-2]

tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[chemical formula 130]

Methanesulfonyl chloride (2.57 mL, 33.3 mmol) and triethylamine (11.6 mL, 83.1 mmol) were added to commercially available N-BOC-3-hydroxyazetidine (4.8 g, 27.7 mmol) in a solution in tetrahydrofuran (100 mL). The reaction liquid was stirred at room temperature for 2 hours. To the reaction liquid was added saturated aqueous sodium bicarbonate solution at room temperature, and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.45 (9H, s), 3.07 (3H, s), 4.03-4.18 (2H, m), 4.22-4.36 (2H, m), 5.12-5.27 ( 1H, m).

[Production example 26-3]

tert-Butyl 3-iodoazetidine-1-carboxylate

[chemical formula 131]

Potassium iodide (51.0 g, 307 mmol) was added to tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate described in Production Example 26-2 under nitrogen atmosphere at room temperature (7.72 g, 30.7 mmol) in a solution in dimethylsulfoxide (80 mL), and the mixture was stirred at 140° C. for 2 hours. The reaction liquid was diluted with diethyl ether and water. The aqueous layer was extracted with diethyl ether. The combined organic layers were successively washed with an aqueous sodium metabisulfite solution and a saturated saline solution, and then dried over anhydrous sodium sulfate. The desiccant was separated by filtration and the resultant was then concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (5.91 g, 68%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.44 (9H, s), 4.25-4.33 (2H, m), 4.42-4.51 (1H, m), 4.61-4.69 (2H, m).

[Production example 26-4]

tert-butyl 3-(4-(ethoxycarbonyl)phenyl)azetidine-1-carboxylate

[chemical formula 132]

1,2-Dibromoethane (0.286 mL, 3.32 mmol) was added to a suspension of zinc powder (2.12 g, 32.4 mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen atmosphere. The liquid mixture was stirred at 65°C for 10 minutes. The reaction liquid was allowed to stand to cool to room temperature, then trimethylchlorosilane (0.400 mL, 3.13 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (5.91 g, 20.9 mmol) in tetrahydrofuran (10 mL) described in Production Example 26-3 was added to the reaction liquid over 5 minutes , and the mixture was stirred at room temperature for 40 min (Solution A). Tris(dibenzylideneacetone)dipalladium(0) (382 mg, 0.418 mmol) and tris-2-furan phosphine (402 mg, 1.73 mmol) in tetrahydrofuran (10 mL) were dissolved at room temperature under nitrogen atmosphere The solution was stirred for 15 minutes, and then solution A prepared previously was added at room temperature. Subsequently, a solution of ethyl 4-iodobenzoate (6.92 g, 25.1 mmol) in tetrahydrofuran (18.5 mL) was added at room temperature under nitrogen atmosphere. The reaction liquid was stirred overnight at 65°C. The reaction liquid was allowed to stand to cool to room temperature, then filtered through celite, and the resultant was washed with ethyl acetate. The filtrate was successively washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1) to obtain the title compound (4.35 g, 68% ).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40 (3H, t, J=8.0Hz), 1.47 (9H, s), 3.71-3.84 (1H, m), 3.95-4.02 (2H, m) , 4.32-4.44 (4H, m), 7.34-7.42 (2H, m), 7.98-8.07 (2H, m).

[Production example 26-5]

4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzoic acid

[chemical formula 133]

2M sodium hydroxide solution (28.5 mL, 57.0 mmol) was added to 3-(4-(ethoxycarbonyl)phenyl)azetidine-1-carboxylic acid described in Production Example 26-4 at 25°C A solution of tert-butyl ester (4.35 g, 14.2 mmol) in tetrahydrofuran (32 mL) and methanol (7 mL). The reaction liquid was stirred at 60°C for 1 hour. To the reaction liquid was added 2M hydrochloric acid (28.5 mL), and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (3.4 g, 86%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.48 (9H, s), 3.71-3.88 (1H, m), 3.96-4.04 (2H, m), 4.37 (2H, t, J=8.6Hz) , 7.42 (2H, d, J = 8.4 Hz), 8.09 (2H, d, J = 8.3 Hz).

[Production Example 26-6]

5-((2-(4-(azetidin-3-yl)benzamide)pyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl Amyl-1H-indole-1-carboxamide

[chemical formula 134]

3-(4-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indole-5 -yl)oxy)pyridin-2-yl)carbamoyl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (279 mg, 0.443 mmol) was dissolved in dichloromethane (8.0 mL) and dissolved in Trifluoroacetic acid (1.6 mL) was added at 0°C. The mixture was stirred at room temperature for 40 minutes, and then concentrated in vacuo, the residue was dissolved in dichloromethane and triethylamine, and the resultant was subjected to NH silica gel column chromatography (ethyl acetate:methanol= 97:3-4:1) to obtain the title compound (215 mg, 92%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.07 (3H, t, J=7.0Hz), 3.05 (3H, d, J=4.8Hz), 3.40 (2H, q, J=7.0Hz), 3.61-3.65(2H, m), 3.81(2H, t, J=7.0Hz), 3.93-4.09(3H, m), 4.15-4.20(2H, m), 5.51-5.63(1H, m), 6.53( 1H, d, J = 3.7Hz), 6.61 (1H, dd, J = 5.9, 2.2Hz), 7.24-7.28 (1H, m), 7.33 (1H, s), 7.40 (2H, d, J = 8.1Hz ), 7.82 (2H, d, J = 8.1Hz), 7.91 (1H, d, J = 2.2Hz), 8.01 (1H, s), 8.09 (1H, d, J = 5.5Hz), 8.52 (1H, brs ).

[Example 27]

6-(2-ethoxyethoxy)-5-((2-(4-(1-(2-hydroxyethyl)azetidin-3-yl)benzamide)pyridine-4- Base)oxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 135]

Commercially available 2-glycolaldehyde (45.9 mg, 0.765 mmol), sodium triacetoxyborohydride (86 mg, 0.408 mmol), and acetic acid (23 μL, 0.408 mmol) were added to Production Example 26-6 at room temperature 5-((2-(4-(azetidin-3-yl)benzamide)pyridin-4-yl)oxy)-6-(2-ethoxyethoxy) described in -N-Methyl-1H-indole-1-carboxamide (27 mg, 0.051 mmol) in a solution in tetrahydrofuran (2 mL), and the mixture was stirred at the same temperature for 2 hr. To the reaction liquid was added saturated aqueous sodium bicarbonate solution at room temperature, and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (20.0 mg, 68%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.08 (3H, t, J=7.0Hz), 2.68-2.76 (2H, m), 3.06 (3H, d, J=4.8Hz), 3.27-3.34 (2H, m), 3.40 (2H, q, J=7.0Hz), 3.55-3.67 (4H, m), 3.71-3.94 (3H, m), 4.15-4.22 (2H, m), 5.53-5.65 (1H , m), 6.55 (1H, d, J=3.7Hz), 6.62 (1H, dd, J=5.9, 2.2Hz), 7.23-7.29 (1H, m), 7.34 (1H, s), 7.38 (2H, d, J = 8.4Hz), 7.83 (2H, d, J = 8.1Hz), 7.91 (1H, d, J = 2.6Hz), 8.01 (1H, s), 8.09 (1H, d, J = 5.9Hz) , 8.63 (1H, brs).

[Example 28]

6-(2-Ethoxyethoxy)-5-((2-(6-(1-ethylpiperidin-4-yl)nicotinamide)pyridin-4-yl)oxy)-N-methyl Amyl-1H-indole-1-carboxamide

[chemical formula 136]

To 6-(2 -Ethoxyethoxy)-N-methyl-5-((2-(6-(piperidin-4-yl)nicotinamide)pyridin-4-yl)oxy)-1H-indole-1 - A solution of formamide (25 mg, 0.045 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred for 1 hour. To the reaction liquid was added saturated aqueous sodium bicarbonate solution at room temperature, and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (13.6 mg, 52%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.07 (3H, t, J=7.0Hz), 1.13 (3H, t, J=7.1Hz), 1.78-1.93 (2H, m), 1.94-2.15 (4H, m), 2.46 (2H, q, J = 7.3Hz), 2.74-2.86 (1H, m), 3.00-3.17 (5H, m), 3.40 (2H, q, J = 7.1Hz), 3.63 ( 2H,t,J=4.8Hz), 4.18(2H,t,J=4.8Hz), 5.45-5.57(1H,m), 6.56(1H,d,J=3.3Hz), 6.61(1H,dd,J =5.9, 1.5Hz), 7.20-7.39 (3H, m), 7.84-7.92 (1H, m), 8.02 (1H, s), 8.05-8.15 (2H, m), 8.49 (1H, s), 8.93- 9.07 (1H, m).

The starting material 6-(2-ethoxyethoxy)-N-methyl-5-((2-(6-(piperidin-4-yl)nicotinamide)pyridin-4-yl was synthesized by )oxy)-1H-indole-1-carboxamide.

[Production Example 28-1]

5-methyl 5',6'-dihydro-[2,4'-bipyridine]-1',5(2'H)-dicarboxylic acid 1'-tert-butyl ester

[chemical formula 137]

N,N-Dimethylformamide (100 mL) was added to commercially available 1-N-BOC-4-(4,4,5,5-tetramethyl-[1,3,2]dioxane Pentaboran-2-yl)-3,6-dihydro-2H-pyridine (4.68 g, 15.1 mmol), commercially available methyl 6-chloronicotinate (2.81 g, 16.4 mmol), 1,1′ - in bis(diphenylphosphino)ferrocenepalladium(II) dichloride (1.17g, 1.60mmol), and potassium carbonate (7.02g, 50.8mmol). The reaction liquid was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The reaction liquid was allowed to stand to cool to room temperature, and then diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with dilute ammonia solution and saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (1.07 g, 22%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.49 (9H, s), 2.59-2.73 (2H, m), 3.66 (2H, t, J=5.5Hz), 3.95 (3H, s), 4.17 (2H, d, J = 2.9Hz), 6.79 (1H, dt, J = 3.4, 1.8Hz), 7.44 (1H, d, J = 8.4Hz), 8.25 (1H, dd, J = 8.4, 2.2Hz) , 9.15 (1H, dd, J=2.2, 0.7 Hz).

[Production Example 28-2]

Methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)nicotinate

[chemical formula 138]

10% palladium-carbon (water content, 50%) (213 mg) was added to 5-methyl 5′,6′-dihydro-[2,4′-bipyridine]- 1', 5(2'H)-dicarboxylic acid 1'-tert-butyl ester (1.06g, 3.33mmol) in a solution in ethanol (71mL) and tetrahydrofuran (12mL), and the mixture was heated at room temperature under hydrogen Stir under atmosphere for 2 hours. The mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to quantitatively obtain the title compound.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.48 (9H, s), 1.73 (2H, qd, J=12.6, 4.4Hz), 1.88-1.97 (2H, m), 2.76-2.98 (3H, m), 3.94 (3H, s), 4.27 (2H, brs), 7.22-7.26 (1H, m), 8.23 (1H, dd, J=8.4, 2.2Hz), 9.09-9.18 (1H, m).

[Production Example 28-3]

6-(1-(tert-butoxycarbonyl)piperidin-4-yl)nicotinic acid

[chemical formula 139]

2M sodium hydroxide solution (20 mL) was added to methyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)nicotinate (1.07 g, 3.32 mmol) described in Production Example 28-2 ) in ethanol (5 mL), and the mixture was stirred for 1 hour. To the reaction liquid was added 2M hydrochloric acid at 0°C. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was isolated by filtration and then the filtrate was concentrated under vacuum to obtain the title compound (534 mg, 52%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.42 (9H, s), 1.58 (2H, qd, J=12.6, 4.4Hz), 1.77-1.89 (2H, m), 2.67-3.04 ( 3H, m), 3.95-4.17 (2H, m), 7.40 (1H, d, J=7.7Hz), 8.16 (1H, dd, J=8.1, 2.2Hz), 8.97 (1H, dd, J=2.2, 0.7Hz).

[Production Example 28-4]

4-(5-((4-((6-(2-ethoxyethoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine-2- Base) carbamoyl) pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester

[chemical formula 140]

At 0°C, oxalyl chloride (74 μL, 0.864 mmol) and one drop of N,N-dimethylformamide were added to 6-(1-(tert-butoxycarbonyl)piperidine as described in Production Example 28-3 pyridin-4-yl) nicotinic acid (80 mg, 0.216 mmol) in dichloromethane (2 mL), and the mixture was stirred for 30 minutes. The reaction liquid was concentrated under vacuum. The residue was dissolved in tetrahydrofuran (2 mL), and triethylamine (301 μL, 2.16 mmol) and 5-((2-aminopyridin-4-yl)oxy) described in Production Example 24-8 were added -6-(2-Ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide (80 mg, 0.216 mmol), and the mixture was stirred for 5 hours. To the reaction liquid was added excess methylamine, and then the mixture was diluted with water and ethyl acetate for segmentation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (80 mg, 56%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.04 (3H, t, J = 7.0Hz), 1.45 (9H, s), 1.68 (2H, qd, J = 12.6, 4.4Hz), 1.83-1.93 (2H, m), 2.69-2.92 (3H, m), 2.96 (3H, d, J=4.8Hz), 3.37 (2H, q, J=7.0Hz), 3.56-3.63 (2H, m), 4.11- 4.15(2H, m), 4.21(2H, brs), 6.10-6.20(1H, m), 6.44(1H, d, J=3.7Hz), 6.58(1H, dd, J=5.7, 2.4Hz), 7.21 (1H, d, J = 7.7Hz), 7.24-7.31 (2H, m), 7.86 (1H, d, J = 2.2Hz), 7.95 (1H, d, J = 5.9Hz), 8.02 (1H, s) , 8.07 (1H, dd, J=8.2, 2.4Hz), 8.96-9.02 (1H, m), 9.20 (1H, brs).

[Production Example 28-5]

6-(2-ethoxyethoxy)-N-methyl-5-((2-(6-(piperidin-4-yl)nicotinamide)pyridin-4-yl)oxy)-1H- Indole-1-carboxamide

[chemical formula 141]

Trifluoroacetic acid (374 μL, 4.86 mmol) was added to 4-(5-((4-((6-(2-ethoxyethoxy)-1- (Methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (80mg, 0.121mmol ) in dichloromethane (3 mL), and the mixture was stirred for 1.5 hours. The reaction liquid was concentrated under vacuum. The residue was dissolved in dichloromethane, and then triethylamine was added to neutralize the trifluoroacetic acid. The solution was concentrated under vacuum and then the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=49:1-17:3) to obtain the title compound (51.3 mg, 76%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.07 (3H, t, J=7.1Hz), 1.72 (2H, qd, J=12.4, 4.0Hz), 1.87-1.97 (2H, m), 2.76 (2H, td, J=12.3, 2.6Hz), 2.84-2.95(1H, m), 2.99(3H, d, J=4.4Hz), 3.16-3.28(2H, m), 3.40(2H, q, J =7.1Hz), 3.59-3.68(2H, m), 4.14-4.20(2H, m), 6.04-6.17(1H, m), 6.48(1H, d, J=3.7Hz), 6.62(1H, dd, J=5.7, 2.4Hz), 7.23-7.29(2H, m), 7.31(1H, s), 7.88(1H, d, J=2.2Hz), 7.98-8.05(2H, m), 8.10(1H, dd , J=8.2, 2.4 Hz), 9.02 (1H, dd, J=2.6, 0.7 Hz).

[Example 29]

(S)-6-(2-ethoxyethoxy)-5-((2-(4-((2-hydroxymethyl)pyrrolidin-1-yl)methyl)benzamide)pyridine- 4-yl)oxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 142]

At room temperature, commercially available L-prolinol (31.3 mg, 0.309 mmol) was added to 5-((2-(4-(chloromethyl)-N-( 4-(Chloromethyl)benzoyl)benzamide)pyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1- formamide (19.6 mg, 0.029 mmol) and N,N-dimethylformamide (500 μL), and the mixture was stirred under nitrogen atmosphere for 17.5 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, the resulting residue was purified by NH silica gel TLC (ethyl acetate), and the product was collected by filtration and washed with diethyl ether to obtain the title compound (13.3 mg, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.08 (3H, t, J=7.1Hz), 1.65-1.99 (5H, m), 2.23-2.32 (1H, m), 2.71-2.79 (1H, m), 2.92-2.99(1H, m), 3.06(3H, d, J=4.8Hz), 3.37-3.48(4H, m), 3.61-3.69(3H, m), 4.03(1H, d, J= 13.5Hz), 4.16-4.20(2H, m), 5.48-5.56(1H, m), 6.55(1H, d, J=3.7Hz), 6.61(1H, dd, J=5.9, 2.6Hz), 7.24- 7.28(1H, m), 7.34(1H, s), 7.41(2H, d, J=8.4Hz), 7.79-7.84(2H, m), 7.91(1H, d, J=2.2Hz), 8.01(1H , s), 8.10 (1H, d, J=5.5Hz), 8.50 (1H, brs).

The starting material 5-((2-(4-(chloromethyl)-N-(4-(chloromethyl)benzoyl)benzamide)pyridin-4-yl)oxy)- 6-(2-Ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide.

[Production Example 29-1]

5-((2-(4-(chloromethyl)-N-(4-(chloromethyl)benzoyl)benzamide)pyridin-4-yl)oxy)-6-(2-ethoxy Ethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 143]

Under nitrogen atmosphere at 0 °C, triethylamine (300 μL, 2.16 mmol) and commercially available 4-(chloromethyl)benzoyl chloride (221 mg, 1.17 mmol) were added to that described in Production Example 24-8 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide (107mg, 0.289mmol ) and tetrahydrofuran (8.0 mL) in a mixture. The mixture was stirred at room temperature for 1 hour, and then water and ethyl acetate were added to the reaction mixture for segmentation. The organic layer was washed with saturated saline solution and then dried over anhydrous sodium sulfate and then filtered with NH silica gel. The filtrate was concentrated under vacuum to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.11 (3H, t, J=7.0Hz), 3.06 (3H, d, J=4.8Hz), 3.43 (2H, q, J=7.0Hz), 3.56-3.60(2H, m), 4.08-4.12(2H, m), 4.56(4H, s), 5.41-5.49(1H, m), 6.55(1H, d, J=3.7Hz), 6.67(1H, d, J = 2.2Hz), 6.71 (1H, dd, J = 5.9, 2.2Hz), 7.24 (1H, s), 7.25-7.28 (1H, m), 7.34-7.39 (4H, m), 7.69-7.75 (4H, m), 7.98 (1H, s), 8.17 (1H, d, J=5.9Hz).

[Example 30]

5-((2-(4-(((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)benzamide)pyridin-4-yl)oxy)-6- (2-Ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 144]

Commercially available cis-2,6-dimethylpiperazine (32.5 mg, 0.285 mmol) was added to 5-((2-(4-(chloro Methyl)-N-(4-(chloromethyl)benzoyl)benzamide)pyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl- 1H-indole-1-carboxamide (21.1 mg, 0.031 mmol) and N,N-dimethylformamide (500 μL), and the mixture was stirred under nitrogen atmosphere for 13 hours and 20 minutes. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated and the resulting residue was purified by NH silica gel TLC (ethyl acetate), then the product was collected by filtration and washed with diethyl ether to obtain the title compound (14.4 mg, 77%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.02 (6H, d, J=6.2Hz), 1.07 (3H, t, J=7.0Hz), 1.63 (2H, t, J=10.6Hz), 2.69-2.76(2H, m), 2.89-2.99(2H, m), 3.07(3H, d, J=4.8Hz), 3.40(2H, q, J=7.0Hz), 3.52(2H, s), 3.61 -3.65(2H, m), 4.16-4.20(2H, m), 5.45-5.52(1H, m), 6.55(1H, d, J=3.7Hz), 6.60(1H, dd, J=5.9, 2.2Hz ), 7.25-7.27(1H, m), 7.34(1H, s), 7.43(2H, d, J=8.1Hz), 7.79-7.83(2H, m), 7.92(1H, d, J=2.2Hz) , 8.01 (1H, s), 8.10 (1H, d, J=5.9Hz), 8.47 (1H, brs).

[Example 31]

(R)-6-(2-ethoxyethoxy)-5-((2-(5-((3-hydroxypyrrolidin-1-yl)methyl)thiophene-2-carboxamide)pyridine- 4-yl)oxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 145]

Thionyl chloride (2.8 mL, 38.4 mmol) and N,N-dimethylformamide (5.87 μL, 0.076 mmol) were added to 5-(hydroxymethyl)thiophene-2- Formic acid (120mg, 0.759mmol), and the mixture was heated and stirred at 90°C for 2 hours. The reaction mixture was evaporated under vacuum to obtain a crude product A (148 mg).

Triethylamine (191 μL, 1.38 mmol) and a portion of crude product A (74.0 mg, 0.379 mmol) in tetrahydrofuran (1.0 mL) were added at 0° C. under a nitrogen atmosphere to the mixture described in Production Example 24-8 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide (51.1mg, 0.138mmol ) and tetrahydrofuran (1.4 mL) in a mixture. The mixture was stirred at room temperature for 170 minutes, and then water and ethyl acetate were added to the reaction mixture for segmentation. The organic layer was washed with saturated saline solution, then dried over anhydrous sodium sulfate and filtered with NH silica gel, and then the resultant was concentrated under vacuum to obtain a crude product B (86.7 mg).

A portion (17.3 mg) of crude product B was dissolved in N,N-dimethylformamide (1.0 mL), and commercially available (R)-3-hydroxypyrrolidine (24.4 mg, 0.28 mmol), and the mixture was stirred for 17 hours. To the reaction mixture were added water and ethyl acetate for fractionation, and the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by NH silica gel TLC (ethyl acetate), and then the product was collected by filtration and washed with n-hexane to obtain the title compound (9.0 mg, 56%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.07 (3H, t, J=6.8Hz), 1.71-1.81 (1H, m), 2.13-2.24 (1H, m), 2.34-2.43 (1H, m), 2.57-2.64(1H, m), 2.69-2.76(1H, m), 2.87-2.97(1H, m), 3.06(3H, d, J=4.8Hz), 3.39(2H, q, J= 7.3Hz), 3.59-3.64(2H, m), 3.84(2H, s), 4.14-4.19(2H, m), 4.31-4.37(1H, m), 5.48-5.55(1H, m), 6.54(1H , d, J=3.7Hz), 6.61(1H, dd, J=5.9, 2.4Hz), 6.91(1H, d, J=3.5Hz), 7.24-7.28(1H, m), 7.32(1H, s) , 7.47 (1H, d, J = 3.9Hz), 7.78-7.82 (1H, m), 7.99 (1H, s), 8.08 (1H, d, J = 5.7Hz), 8.34 (1H, brs).

[Production example 31-1]

5-(Hydroxymethyl)thiophene-2-carboxylic acid

[chemical formula 146]

Sodium borohydride (218 mg, 5.76 mmol) was added to a solution of commercially available 5-formyl-2-thiophenecarboxylic acid (599 mg, 3.84 mmol) in methanol (19 mL), and the mixture was heated at room temperature Stir under nitrogen atmosphere for 4 hours 30 minutes. Acetone was added to the reaction mixture, and the mixture was concentrated under vacuum. To the residue were added 2M hydrochloric acid and ethyl acetate for fractionation, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the precipitate was washed with diethyl ether and n-hexane to obtain the title compound (529 mg, 87%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.61-4.74 (2H, m), 5.65-72 (1H, m), 6.97-7.7.03 (1H, m), 7.55-7.62 (1H , m), 12.92 (1H, brs).

[Example 32]

6-(3-Methoxypropoxy)-N-methyl-5-((2-(4-(1-methylazetidin-3-yl)benzamide)pyridine-4- base)oxy)-1H-indole-1-carboxamide

[chemical formula 147]

Formaldehyde (12 μL, 0.425 mmol), acetic acid (13 μL, 0.227 mmol), and sodium triacetoxyborohydride (48.0 mg, 0.227 mmol) were added to 5-((2 -(4-(azetidin-3-yl)benzamide)pyridin-4-yl)oxy)-6-(3-methoxypropoxy)-N-methyl-1H-ind Indole-1-carboxamide (15 mg, 0.028 mmol) in solution in tetrahydrofuran (2 mL). The reaction liquid was stirred at room temperature for 1 hour. To the reaction liquid were added saturated aqueous sodium bicarbonate solution and ethyl acetate at room temperature. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (8.8 mg, 57%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.76 (2H, t, J=6.4Hz), 2.25 (3H, s), 2.85 (3H, d, J=4.4Hz), 3.02-3.13 (7H, m), 3.54-3.65 (3H, m), 3.99 (2H, t, J=6.2Hz), 6.64 (1H, d, J=3.3Hz), 6.69 (1H, dd, J=5.9, 2.6 Hz), 7.42(2H, d, J=8.4Hz), 7.46(1H, s), 7.69(1H, d, J=2.6Hz), 7.77(1H, d, J=3.7Hz), 7.92(2H, d, J=8.4Hz), 8.06(1H,s), 8.14-8.19(1H,m), 8.21(1H,d,J=5.9Hz), 10.70(1H,s).

The starting material 5-((2-(4-(azetidin-3-yl)benzamide)pyridin-4-yl)oxy)-6-(3-methoxypropane) was synthesized by Oxy)-N-methyl-1H-indole-1-carboxamide.

[Production Example 32-1]

3-Hydroxy-4-(3-methoxypropoxy)benzaldehyde

[chemical formula 148]

Commercially available 1-bromo-3-methoxypropane (24.0 g, 157 mmol) was added to commercially available 3,4-dihydroxybenzaldehyde (21.7 g, 157 mmol) and carbonic acid at room temperature under nitrogen atmosphere A solution of sodium (25.0 g, 236 mmol) in N,N-dimethylformamide (50 mL). The reaction liquid was stirred at room temperature for 3 days and 4 hours. To the reaction liquid were added 2M hydrochloric acid, ethyl acetate, and water at 0°C. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The insoluble material was separated by filtration with dichloromethane, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1) to obtain the title compound (17.2 g, 52%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.07-2.18 (2H, m), 3.38 (3H, s), 3.59 (2H, t, J=5.9Hz), 4.26 (2H, t, J= 6.2Hz), 6.21 (1H, s), 7.00 (1H, d, J = 8.1Hz), 7.35-7.48 (2H, m), 9.85 (1H, s).

[Production Example 32-2]

3-(Benzyloxy)-4-(3-methoxypropoxy)benzaldehyde

[chemical formula 149]

Potassium carbonate (14.7 g, 106 mmol) and benzyl chloride (12.2 mL, 106 mmol) were added to 3-hydroxy-4-(3-methoxyl as described in Production Example 32-1 at room temperature under nitrogen atmosphere Propoxy)benzaldehyde (17.2 g, 81.7 mmol) in a solution of ethanol (200 mL), and the mixture was stirred at 90° C. for 2 hr. The reaction liquid was cooled to 0°C, and the mixture was diluted with 2M hydrochloric acid, ethyl acetate and water. The organic layer was washed with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-3:7) to obtain the title compound (19.8 g, 81%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.10-2.20 (2H, m), 3.35 (3H, d, J = 0.7Hz), 3.59 (2H, t, J = 6.0Hz), 4.21 (2H , t, J=6.4Hz), 5.18 (2H, s), 6.95-7.09 (1H, m), 7.28-7.50 (7H, m), 9.76-9.87 (1H, m).

[Production example 32-3]

(E)-2-(Benzyloxy)-1-(3-methoxypropoxy)-4-(2-nitrovinyl)benzene

[chemical formula 150]

Ammonium acetate (6.10 g, 79.1 mmol) and nitromethane (8.93 mL, 165 mmol) were added to 3-(benzyloxy)-4-( A solution of 3-methoxypropoxy)benzaldehyde (19.8 g, 65.9 mmol) in acetic acid (52.8 mL). The liquid mixture was stirred under heat at 130°C for 2 hours. The reaction liquid was allowed to stand to cool to room temperature, and then the precipitate was collected by filtration and washed with ethanol to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.07-2.17 (2H, m), 3.35 (3H, s), 3.59 (2H, t, J=6.0Hz), 4.19 (2H, t, J= 6.4Hz), 5.16(2H, s), 6.96(1H, d, J=8.4Hz), 7.05(1H, d, J=1.8Hz), 7.16(1H, dd, J=8.4, 1.8Hz), 7.29 -7.47 (6H, m), 7.91 (1H, d, J=13.5Hz).

[Production Example 32-4]

(E)-1-(Benzyloxy)-2-(3-methoxypropoxy)-4-nitro-5-(2-nitrovinyl)benzene

[chemical formula 151]

At room temperature, 69% nitric acid (16 mL, 249 mmol) was added to (E)-2-(benzyloxy)-1-(3-methoxypropoxy)-4- (2-Nitrovinyl)benzene (22.6 g, 65.9 mmol) in a liquid mixture in acetic acid (150 mL). The liquid mixture was stirred at room temperature for 6 hours. The reaction liquid was transferred to an ice bath, and the precipitate was collected by filtration and washed with water to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.10-2.13 (2H, m), 3.36 (3H, s), 3.59 (2H, t, J=5.9Hz), 4.25 (2H, t, J= 6.4Hz), 5.27(2H, s), 6.93(1H, s), 7.24(1H, d, J=13.6Hz), 7.34-7.46(5H, m), 7.78(1H, s), 8.52-8.62( 1H, m).

[Production example 32-5]

6-(3-Methoxypropoxy)-1H-indol-5-ol

[chemical formula 152]

At room temperature, 10% palladium-carbon (water content, 50%) (8 g) was added to (E)-1-(benzyloxy)-2-(2-methoxyl) described in Production Example 32-4 Propoxy)-4-nitro-5-(3-nitrovinyl)benzene (19.6 g, 50.5 mmol) in methanol (300 mL). The liquid mixture was stirred at room temperature under hydrogen atmosphere for 6 hours. The reaction liquid was filtered through celite, and then the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1-1:1) to obtain the title compound (3.81 g, 34%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.05-2.13 (2H, m), 3.40 (3H, s), 3.61 (2H, t, J=6.0Hz), 4.16 (2H, t, J= 6.0Hz), 5.97-6.05(1H, m), 6.36-6.46(1H, m), 6.92(1H, s), 7.08(1H, t, J=2.8Hz), 7.14(1H, s), 7.26( 1H, s), 7.82-8.06 (1H, m).

[Production example 32-6]

N-(4-((6-(3-methoxypropoxy)-1H-indol-5-yl)oxy)pyridin-2-yl)acetamide

[chemical formula 153]

Dimethylsulfoxide (25 mL) was added to 6-(3-methoxypropoxy)-1H-indol-5-ol (3.81 g, 17.2mmol), N-(4-chloropyridin-2-yl)acetamide (3.23g, 18.9mmol) described in Production Example 1-5, and potassium tert-butoxide (2.12g, 18.9mmol) in the mixture. The liquid mixture was stirred at 150°C for 14 hours. The reaction liquid was cooled to room temperature, and ethyl acetate and water were then added. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=49:1) to obtain the title compound (2.83 g, 46%) .

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.85-1.91 (2H, m), 2.13 (3H, s), 3.20 (3H, s), 3.24 (2H, t, J=6.2Hz), 4.02 (2H,t,J=6.2Hz), 6.44-6.49(1H,m), 6.51-6.56(1H,m), 6.95-7.02(1H,m), 7.10-7.18(1H,m), 7.31-7.38 (1H, m), 7.71-7.82 (1H, m), 7.97-8.06 (1H, m), 8.20-8.30 (1H, m), 8.36-8.52 (1H, m).

[Production example 32-7]

4-((6-(3-methoxypropoxy)-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 154]

2M sodium hydroxide solution (30 mL) was added to N-(4-((6-(3-methoxypropoxy)-1H-ind Indol-5-yl)oxy)pyridin-2-yl)acetamide (2.8 g, 7.88 mmol) in methanol (30 mL). The liquid mixture was stirred under reflux at 75°C for 2 hours. The reaction liquid was allowed to stand to cool to room temperature, and then ethyl acetate and water were added. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:9-0:1-ethyl acetate:methanol=49:1) to obtain the title compound (2.24 g, 91%) .

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.75-1.92 (2H, m), 3.23 (3H, s), 3.28 (2H, t, J=6.0Hz), 4.03 (2H, t, J= 6.0Hz), 4.30(2H, s), 5.89(1H, d, J=2.2Hz), 6.29(1H, dd, J=5.9, 2.2Hz), 6.46-6.53(1H, m), 7.01(1H, s), 7.16 (1H, dd, J = 3.3, 2.6Hz), 7.35 (1H, s), 7.88 (1H, d, J = 5.9Hz), 8.14-8.26 (1H, m).

[Production example 32-8]

5-((2-aminopyridin-4-yl)oxy)-6-(3-methoxypropoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 155]

50%-72% oily sodium hydride (308 mg) was added to 4-((6-(3-methoxypropoxy)-1H -Indol-5-yl)oxy)pyridin-2-amine (2.23 g, 7.12 mmol) in solution in N,N-dimethylformamide (30 mL). The reaction liquid was stirred for 10 minutes, then methyl phenylcarbamate (1.40 g, 9.25 mmol) described in Production Example 1-7 was added, and the resultant was further stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction liquid. The organic layer was washed successively with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=9:1-0:1) to obtain the title compound (2.44 g, 93%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.73-1.86 (2H, m), 2.81-2.87 (3H, m), 3.12 (3H, d, J=1.8Hz), 3.16-3.24 ( 2H, m), 3.98(2H, t, J=5.7Hz), 5.62-5.71(1H, m), 5.78(2H, s), 6.06-6.15(1H, m), 6.61(1H, dd, J= 3.5, 1.7Hz), 7.36 (1H, d, J = 1.8Hz), 7.71-7.78 (2H, m), 7.98-8.04 (1H, m), 8.10-8.22 (1H, m).

[Production example 32-9]

3-(4-((4-((6-(3-methoxypropoxy)-1-(methylcarbamoyl)-1H-indol-5-yl)oxy)pyridine-2- Base) carbamoyl) phenyl) azetidine-1-carboxylic acid tert-butyl ester

[chemical formula 156]

Thionyl chloride (118 μL, 1.62 mmol) was added to a solution of benzotriazole (193 mg, 1.62 mmol) in dichloromethane (5 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 minutes. To the reaction liquid was added 4-(1-(tert-butoxycarbonyl)azetidin-3-yl)benzoic acid (300 mg, 1.08 mmol) described in Production Example 26-5, and The mixture was stirred for an additional 1 hour. The reaction liquid was filtered through anhydrous sodium sulfate on a glass filter, and the anhydrous sodium sulfate was washed with dichloromethane. Under a nitrogen atmosphere at 0°C, triethylamine (748 µL, 5.40 mmol), 4-dimethylaminopyridine (6.60 mg, 0.054 mmol), and 5-((( 2-aminopyridin-4-yl)oxy)-6-(3-methoxypropoxy)-N-methyl-1H-indole-1-carboxamide (200mg, 0.54mmol) in tetrahydrofuran (10mL ) was added to the resulting dichloromethane solution, and the mixture was stirred for 4 hours and 20 minutes. The reaction liquid was diluted with ethyl acetate and water. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and the filtrate was then concentrated under vacuum. To the residue were added tetrahydrofuran and an excess methylamine tetrahydrofuran solution, and the mixture was stirred at room temperature. The liquid mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1) to obtain the title compound (146 mg, 43%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.43-1.51 (9H, m), 1.80-1.95 (2H, m), 2.95 (3H, d, J=4.8Hz), 3.17 (3H, s) , 3.20-3.27(2H, m), 3.69-3.82(1H, m), 3.95(2H, dd, J=8.6, 6.0Hz), 4.05-4.17(2H, m), 4.33(2H, t, J= 8.6Hz), 6.13-6.25(1H, m), 6.44(1H, d, J=3.7Hz), 6.63(1H, dd, J=5.7, 2.4Hz), 6.97(1H, s), 7.24(2H, d, J = 3.7Hz), 7.38 (2H, d, J = 8.4Hz), 7.83 (2H, d, J = 8.4Hz), 7.88 (1H, d, J = 2.6Hz), 8.01-8.09 (2H, m), 8.79-9.00 (1H, m).

[Production example 32-10]

5-((2-(4-(azetidin-3-yl)benzamide)pyridin-4-yl)oxy)-6-(3-methoxypropoxy)-N-methyl Amyl-1H-indole-1-carboxamide

[chemical formula 157]

Trifluoroacetic acid (713 μL, 9.25 mmol) was added at room temperature to 3-(4-((4-((6-(3-methoxypropoxy)-1- (Methylcarbamoyl)-1H-indol-5-yl)oxy)pyridin-2-yl)carbamoyl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (146mg, 0.231mmol ) in a solution in dichloromethane (5 mL). The reaction liquid was stirred for 1.5 hours, and then the resultant was concentrated under vacuum. The residue was dissolved in dichloromethane and triethylamine to neutralize trifluoroacetic acid, and then the resultant was concentrated under vacuum. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=49:1-17:3) to obtain the title compound (96.2 mg, 79%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.82-1.95 (2H, m), 3.06 (3H, d, J = 4.8Hz), 3.19 (3H, s), 3.24 (2H, t, J = 6.4Hz), 3.79-4.00(5H, m), 4.11(2H, t, J=6.0Hz), 5.56-5.64(1H, m), 6.55(1H, d, J=3.7Hz), 6.61(1H, dd, J=5.9, 2.2Hz), 7.21-7.29(1H, m), 7.34(1H, s), 7.41(2H, d, J=8.4Hz), 7.84(2H, d, J=8.4Hz), 7.92 (1H, d, J = 2.2Hz), 8.00 (1H, s), 8.10 (1H, d, J = 5.9Hz), 8.56-8.68 (1H, m).

[Example 33]

5-((2-(4-(1-ethylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(3-fluoropropoxy)-N-methyl -1H-Indole-1-carboxamide

[chemical formula 158]

Benzotriazole (37.8 mg, 0.317 mmol) was dissolved in dichloromethane (2.0 mL), thionyl chloride (24 μL, 0.322 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (82 mg, 0.269 mmol) described in Production Example 1-12 at room temperature, and The mixture was stirred for 20 minutes. The reaction mixture was filtered through a glass filter completely covered with anhydrous sodium sulfate and then the anhydrous sodium sulfate was washed with dichloromethane, and the filtrate was added at 0°C to the 5-((2-aminopyridin-4-yl)oxy)-6-(3-fluoropropoxy)-N-methyl-1H-indole-1-carboxamide (34.4mg, 0.096mmol) , triethylamine (133 L, 0.960 mmol), and 4-dimethylaminopyridine (1.17 mg, 0.0096 mmol) in a mixture of tetrahydrofuran (1.5 mL), and the mixture was stirred at room temperature for 320 minutes. Water and ethyl acetate were added to the reaction mixture for segmentation, and then the organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The resultant was purified by NH silica gel column chromatography, and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran, an excess of 9.8M methylamine methanol solution was added at room temperature, and the mixture was stirred for 50 minutes. The reaction mixture was concentrated under vacuum, the residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-3:7-0:1 ) for purification. The target fractions were concentrated under vacuum to obtain a crude product A (46.3 mg).

The crude product A (46.3 mg) was dissolved in dichloromethane (1.25 mL), and trifluoroacetic acid (250 μL) was added at 0°C. The mixture was stirred at room temperature for 20 minutes and then concentrated under vacuum, then the residue was dissolved in dichloromethane-triethylamine, and the resultant was subjected to NH silica gel column chromatography (ethyl acetate:methanol= 97:3-4:1) for purification. The target fractions were concentrated under vacuum to obtain a crude product B (35.8 mg).

To a mixture of a portion of crude product B (9.0 mg, 0.016 mmol) and tetrahydrofuran (500 μL) was added sodium triacetoxyborohydride (10.4 mg, 0.049 mmol) and acetaldehyde (2.17 mg, 0.049 mmol) at room temperature ), and the mixture was stirred at room temperature for 140 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated and the resulting residue was purified by NH silica gel TLC (ethyl acetate). The resulting solid was washed with diethyl ether to obtain the title compound (6.7 mg, 49%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.14 (3H, t, J=7.1Hz), 1.76-1.91 (4H, m), 1.93-2.12 (4H, m), 2.41-2.64 (3H, m), 3.03-3.17(5H, m), 4.16(2H, t, J=6.0Hz), 4.24(1H, t, J=5.9Hz), 4.36(1H, t, J=5.7Hz), 5.46- 5.57(1H, m), 6.55(1H, d, J=3.3Hz), 6.58(1H, dd, J=5.9, 2.2Hz), 7.24(1H, d, J=3.7Hz), 7.31-7.36(3H , m), 7.80(2H, d, J=8.1Hz), 7.90(1H, d, J=2.2Hz), 8.02(1H, s), 8.10(1H, d, J=5.9Hz), 8.49(1H , brs).

The starting material 5-((2-aminopyridin-4-yl)oxy)-6-(3-fluoropropoxy)-N-methyl-1H-indole-1-carboxamide was synthesized by the following method.

[Production Example 33-1]

4-(3-fluoropropoxy)-3-hydroxybenzaldehyde

[chemical formula 159]

Suspend commercially available 3,4-dihydroxybenzaldehyde (6.5 g, 47.1 mmol) and potassium carbonate (6.83 g, 49.4 mmol) in N, N-dimethylformamide (30 mL), and then 3-Fluoropropyl 4-methylbenzenesulfonate (11.3 g, 48.4 mmol) described in Production Example 4-1 was added under a nitrogen atmosphere, and the mixture was stirred for 37 hours. The mixture was cooled to 0°C, and then 2M hydrochloric acid, ethyl acetate and water were added for fractionation. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:1-1:1). The target fractions were concentrated under vacuum to obtain the title compound (4.62 g, 50%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.23 (1H, quin, J=5.9Hz), 2.30 (1H, quin, J=5.8Hz), 4.31 (2H, t, J=6.2Hz), 4.60(1H, t, J=5.6Hz), 4.72(1H, t, J=5.6Hz), 5.70(1H, s), 6.99(1H, d, J=8.2Hz), 7.41-7.47(2H, m ), 9.85 (1H, s).

[Production Example 33-2]

3-(Benzyloxy)-4-(3-fluoropropoxy)benzaldehyde

[chemical formula 160]

Potassium carbonate (3.87 g, 28.0 mmol) and benzyl chloride (3.2 mL, 27.8 mmol) were added to 4-(3-fluoropropoxy) described in Production Example 33-1 at room temperature under nitrogen atmosphere - a suspension of 3-hydroxybenzaldehyde (4.62 g, 23.3 mmol) in ethanol (46 mL), and the mixture was stirred at 90° C. for 1.5 hr. The reaction mixture was cooled to 0 °C, then 2M hydrochloric acid, ethyl acetate and water were added for partitioning. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2-1:1). The target fractions were concentrated in vacuo to obtain the title compound (6.14 g, 91%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.22 (1H, quin, J=5.9Hz), 2.29 (1H, quin, J=5.9Hz), 4.25 (2H, t, J=6.2Hz), 4.62(1H, t, J=5.7Hz), 4.74(1H, t, J=5.7Hz), 5.18(2H, s), 7.02(1H, d, J=8.1Hz), 7.29-7.50(7H, m ), 9.83 (1H, s).

[Production Example 33-3]

(E)-2-(Benzyloxy)-1-(3-fluoropropoxy)-4-(2-nitrovinyl)benzene

[chemical formula 161]

3-(Benzyloxy)-4-(3-fluoropropoxy)benzaldehyde (6.14 g, 21.3 mmol) described in Production Example 33-2 was dissolved in acetic acid (17.0 mL), and then Ammonium acetate (1.97 g, 25.6 mmol) and nitromethane (2.8 mL, 51.7 mmol) were added under nitrogen atmosphere, and the mixture was heated and stirred at 130° C. for 2 hrs. The mixture was cooled to room temperature, and the precipitate was collected by filtration and washed with a small amount of ethanol to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.21 (1H, quin, J=6.0Hz), 2.28 (1H, quin, J=5.9Hz), 4.22 (2H, t, J=6.0Hz), 4.62 (1H, t, J = 5.7Hz), 4.73 (1H, t, J = 5.7Hz), 5.15 (2H, s), 6.95 (1H, d, J = 8.4Hz), 7.06 (1H, d, J = 1.8 Hz), 7.17 (1H, dd, J = 8.2, 2.0 Hz), 7.29-7.49 (6H, m), 7.91 (1H, d, J = 13.5 Hz).

[Production Example 33-4] 6-(3-fluoropropoxy)-1H-indol-5-ol

[chemical formula 162]

Fuming nitric acid (4.80 mL, 107 mmol) was added to (E)-2-(benzyloxy)-1-(3-fluoropropoxy)-4-(2-nitro Vinyl)benzene (7.06 g, 21.3 mmol) and acetic acid (61 mL) were in a mixture in an ice bath, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured onto ice, the precipitate was collected by filtration, and then the resultant was washed with a small amount of a liquid mixture of acetic acid and ethanol to obtain a crude product (8.02 g).

The crude product (8.02 g) was suspended in methanol (150 mL), then 10% palladium-carbon (water content, 50%) (2.27 g) was added, and the mixture was stirred under a hydrogen atmosphere for 6 hr. The inside of the reaction system was replaced with nitrogen, and then the mixture was diluted with methanol. The catalyst was filtered off with celite, the filtrate was concentrated in vacuo, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1). The target fractions were concentrated in vacuo to obtain the title compound (1.47 g, 33%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.22 (1H, quin, J=5.9Hz), 2.29 (1H, quin, J=5.9Hz), 4.23 (2H, t, J=6.0Hz), 4.62(1H, t, J=5.7Hz), 4.74(1H, t, J=5.7Hz), 5.42(1H, s), 6.42(1H, ddd, J=3.1, 2.2, 0.9Hz), 6.91(1H , s), 7.09 (1H, dd, J = 3.1, 2.4 Hz), 7.15 (1H, s), 7.94 (1H, brs).

[Production example 33-5]

4-((6-(3-fluoropropoxy)-1H-indol-5-yl)oxy)pyridin-2-amine

[chemical formula 163]

6-(3-fluoropropoxy)-1H-indol-5-ol (1.47 g, 7.04 mmol) described in Production Example 33-4, N-(4 -Chloropyridin-2-yl)acetamide (1.32g, 7.74mmol), and potassium tert-butoxide (864mg, 7.70mmol) were dissolved in dimethyl sulfoxide (7.0mL), and the mixture was heated and heated at 160°C Stir under nitrogen atmosphere for 4.5 hours. The reaction liquid was cooled to room temperature, and then water and ethyl acetate were added for segmentation. The aqueous layer was extracted with ethyl acetate again, and then the combined organic layers were washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, the filtrate was concentrated in vacuo, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1-0:1-ethyl acetate: Methanol=99:1-9:1) for purification. The target fractions were concentrated under vacuum to obtain a crude product (177 mg).

The obtained crude product (177 mg) was dissolved in methanol (2.5 mL), 2M sodium hydroxide solution (2.5 mL) was added at room temperature under nitrogen atmosphere, and the mixture was heated and stirred at 70° C. for 2 hr. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added for segmentation. The organic layer was washed with saturated saline solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated in vacuo, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=2:3-1:4-0:1-ethyl acetate: methanol=19:1) for purification. The target fractions were concentrated in vacuo to obtain the title compound (49.4 mg, 2.3%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.95-2.11 (2H, m), 4.07 (2H, t, J=5.9Hz), 4.28-4.47 (4H, m), 5.88 (1H, d, J=2.2Hz), 6.28(1H, dd, J=5.9, 2.2Hz), 6.48-6.52(1H, m), 7.02(1H, s), 7.16-7.20(1H, m), 7.35(1H, s ), 7.88 (1H, d, J=5.9Hz), 8.25 (1H, brs).

[Production example 33-6]

5-((2-aminopyridin-4-yl)oxy)-6-(3-fluoropropoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 164]

4-((6-(3-fluoropropoxy)-1H-indol-5-yl)oxy)pyridin-2-amine (49.4 mg, 0.164 mmol) described in Production Example 33-5 was dissolved To N,N-dimethylformamide (1.6 mL) was added 50%-72% oily sodium hydride (14.9 mg) at 0°C under nitrogen atmosphere, and the mixture was stirred at room temperature for 15 min. The mixture was cooled to 0°C again, methyl phenylcarbamate (62.0 mg, 0.41 mmol) described in Production Example 1-7 was added, and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture were added saturated aqueous ammonium chloride, water and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was concentrated in vacuo, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:4-0:1-ethyl acetate:methanol=99: 1-9:1) for purification. The target fractions were concentrated in vacuo to obtain the title compound (34.4 mg, 59%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.95-2.11 (2H, m), 3.07 (3H, dd, J=4.7, 1.2), 4.12-4.17 (2H, m), 4.29 (1H, t , J=5.8Hz), 4.38-4.52 (3H, m), 5.50 (1H, brs), 5.87 (1H, d, J=2.0Hz), 6.26 (1H, dd, J=6.0, 2.1Hz), 6.56 (1H, d, J = 3.7Hz), 7.23-7.27 (1H, m), 7.29 (1H, s), 7.87 (1H, d, J = 6.0Hz), 8.00 (1H, s).

According to Examples 1 to 33, the example compounds illustrated in Tables 1 and 2 were obtained from 5-((2-aminopyridin-4-yl)oxy)-6-methoxy- Synthesized from N-methyl-1H-indole-1-carboxamide.

[Table 1]

[Table 2]

According to Examples 1 to 33, the example compounds illustrated in Table 3 were obtained from 5-((2-aminopyridin-4-yl)oxy)-6-ethoxy-N-methanol described in Production Example 15-7 Synthesized from -1H-indole-1-carboxamide.

[table 3]

According to Examples 1 to 33, the example compounds illustrated in Table 4 were obtained from 5-((2-aminopyridin-4-yl)oxy)-6-isopropoxy-N- Synthesized from methyl-1H-indole-1-carboxamide.

[Table 4]

According to Examples 1 to 33, the example compounds illustrated in Table 5 were obtained from 5-((2-aminopyridin-4-yl)oxy)-6-(3-fluoropropoxy) described in Production Example 33-6 )-N-methyl-1H-indole-1-carboxamide.

[table 5]

According to Examples 1 to 33, the example compounds illustrated in Table 6 were prepared from 5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy) as described in Production Example 20-7 Oxy)-N-methyl-1H-indole-1-carboxamide was synthesized.

[Table 6]

According to Examples 1 to 33, the example compounds illustrated in Table 7 and Table 8 were obtained from 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethane) described in Production Example 24-8 Oxyethoxy)-N-methyl-1H-indole-1-carboxamide.

[Table 7]

[Table 8]

According to Examples 1 to 33, the example compounds illustrated in Table 9 were obtained from 5-((2-aminopyridin-4-yl)oxy)-6-(3-methoxypropane as described in Production Example 32-8 Oxy)-N-methyl-1H-indole-1-carboxamide was synthesized.

[Table 9]

[instance 131]

6-methoxy-5-((2-(4-(1-(2-methoxyacetyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-N- Methyl-1H-indole-1-carboxamide

[chemical formula 165]

Triethylamine (33 μL, 12.1 mmol) and methoxyacetyl chloride (12.5 mg, 0.115 mmol) were added to 6-methoxy-N-methyl-5-((2-(4 -(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (13.4 mg, 0.027 mmol) and tetrahydrofuran (1.0 mL) in a mixture , and the mixture was stirred at room temperature for 3.5 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-9:1). The target fractions were concentrated in vacuo, and the solid was washed with diethyl ether to obtain the title compound (10.2 mg, 67%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.50-1.73 (2H, m), 1.87-1.98 (2H, m), 2.62-2.75 (1H, m), 2.76-2.89 (1H, m), 3.02-3.19(4H, m), 3.45(3H, s), 3.86(3H, s), 3.97-4.03(1H, m), 4.06-4.21(2H, m), 4.71-4.81(1H, m), 5.47-5.55 (1H, m), 6.55 (1H, d, J=3.7Hz), 6.60 (1H, dd, J=5.8, 2.3Hz), 7.23 (1H, d, J=3.8Hz), 7.27-7.34 (3H, m), 7.81 (2H, d, J = 8.4Hz), 7.91 (1H, d, J = 2.4Hz), 8.03 (1H, s), 8.10 (1H, d, J = 5.7Hz), 8.49 (1H, brs).

According to Example 131, the example compound illustrated in Table 10 was obtained from 6-methoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide) described in Example 1 ) pyridin-4-yl)oxy)-1H-indole-1-carboxamide.

[Table 10]

[instance 133]

5-((2-(4-(1-(2-Dimethylamino)acetyl)piperidinyl-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy -N-Methyl-1H-indole-1-carboxamide

[chemical formula 166]

N,N-Dimethylformamide (0.5 mL) and N,N-diisopropylethylamine (24 μL, 0.137 mmol) were added to the 6-methoxy-N-methyl- 5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (13.7mg, 0.027mmol), O- (7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.3mg, 0.043mmol) and N,N-dimethylglycine (5.5mg, 0.053mmol) in a mixture, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-9:1). The target fractions were concentrated under vacuum, and the solid was washed with diethyl ether to obtain the title compound (13.7 mg, 85%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.49-1.74 (2H, m), 1.85-1.97 (2H, m), 2.32 (6H, s), 2.60-2.71 (1H, m), 2.76- 2.87(1H, m), 3.04-3.26(6H, m), 3.87(3H, s), 4.20-4.32(1H, m), 4.71-4.83(1H, m), 5.45-5.54(1H, m), 6.54-6.57 (1H, m), 6.60 (1H, dd, J=5.8, 2.3Hz), 7.24 (1H, d, J=3.7Hz), 7.28-7.34 (3H, m), 7.82 (2H, d, J=8.6Hz), 7.92 (1H, d, J=2.4Hz), 8.04 (1H, s), 8.10 (1H, d, J=5.7Hz), 8.49 (1H, brs).

According to Example 133, the example compound illustrated in Table 11 was obtained from 6-methoxy-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide) described in Example 1 ) pyridin-4-yl)oxy)-1H-indole-1-carboxamide.

[Table 11]

[instance 135]

6-Ethyl-5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-N-methyl- 1H-Indole-1-carboxamide

[chemical formula 167]

To 6-ethyl-N-methyl-5 -((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (15.6 mg, 0.031 mmol) and tetrahydrofuran (1.0 mL), and the mixture was stirred at room temperature for 15 hours and 50 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-9:1-17:3). The target fractions were concentrated in vacuo to obtain the title compound (13.2 mg, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.24 (3H, t, J=7.5Hz), 1.71-1.92 (5H, m), 2.16-2.26 (2H, m), 2.55-2.72 (5H, m), 3.01-3.13(5H, m), 3.64(2H, t, J=5.3Hz), 5.46-5.53(1H, m), 6.52(1H, dd, J=5.9, 2.2Hz), 6.56(1H , d, J = 3.7Hz), 7.24-7.29 (1H, m), 7.34 (2H, d, J = 8.4Hz), 7.37 (1H, d, J = 3.7Hz), 7.82 (2H, d, J = 8.1 Hz), 7.98 (1H, d, J = 2.2 Hz), 8.10 (1H, d, J = 5.9 Hz), 8.12 (1H, s), 8.49 (1H, brs).

The starting material 6-ethyl-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H- was synthesized by the following method Indole-1-carboxamide.

[Production Example 135-1]

6-Ethylindoline

[chemical formula 168]

Dissolve commercially available 3-ethylaniline (10.1 g, 83.3 mmol) in ethanol (40 mL), then add sodium bicarbonate (7.00 g, 83.3 mmol) and bromoacetaldehyde diethyl acetal (8.44 mL , 54.8 mmol), and the mixture was heated and stirred at 80° C. for 80 hours. Water was added to the reaction mixture for fractionation. The aqueous layer was extracted three times with ethyl acetate, and then the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under vacuum. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1). The target fractions were concentrated under vacuum to obtain a crude product A (11 g).

A part (10 g) of the obtained crude product A was dissolved in trifluoroacetic acid (45 mL), anhydrous trifluoroacetic acid (45 mL) was added at 4° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added trifluoroacetic acid (60 L), and the mixture was stirred at 75°C for 2.5 hrs. After concentration under vacuum, the aqueous layer was extracted three times with ethyl acetate, and then the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under vacuum. The resulting residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=3:1). The target fractions were concentrated under vacuum to obtain a crude product B (3 g).

A part (1.5 g) of the obtained crude product B was dissolved in acetic acid (50 mL), sodium cyanoborohydride (1.30 g, 20.7 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate for fractionation. The aqueous layer was extracted three times with ethyl acetate, and then the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1). The target fractions were concentrated in vacuo to obtain the title compound (560 mg, 15%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.20 (3H, t, J=7.6Hz), 2.55 (2H, q, J=7.7Hz), 2.99 (2H, t, J=8.4Hz), 3.54 (2H, t, J=8.3Hz), 3.72 (1H, brs), 6.43-6.61 (2H, m), 6.93-7.07 (1H, m).

[Production Example 135-2]

6-Ethyl-1H-indol-5-ol

[chemical formula 169]

Potassium nitrosodisulfonate (6.82 g, 25.4 mmol) was dissolved in 0.1 M potassium phosphate buffer (450 mL), and then 6- Ethylindoline (1.7 g, 11.5 mmol), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added 2M sodium hydroxide for fractionation. The aqueous layer was extracted three times with ethyl acetate, and then the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1). The target fractions were concentrated in vacuo to obtain the title compound (560 mg, 30%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.29 (3H, t, J = 7.5Hz), 2.74 (2H, q, J = 7.5Hz), 4.50 (1H, s), 6.34-6.43 (1H , m), 6.99 (1H, s), 7.07-7.18 (2H, m), 7.95 (1H, brs).

Example compounds illustrated in Table 12 (comprising starting material 6-ethyl-N-methyl-5-((2-(4-(piperidin-4-yl)benzyl) from Example 135) according to Examples 1 to 33 Amide) pyridin-4-yl) oxy)-1H-indole-1-carboxamide) was obtained from 6-ethyl-1H-indole-5-ol described in Production Example 135-2 and in Production Example Synthesized from N-(4-chloropyridin-2-yl)acetamide described in 1-5.

[Table 12]

[instance 140]

5-((2-(4-((4-hydroxypiperidin-1-yl)methyl)benzamide)pyridin-4-yl)oxy)-6-(methoxymethyl)-N- Methyl-1H-indole-1-carboxamide

[chemical formula 170]

Triethylamine (20 μL, 0.144 mmol) and commercially available 4-(chloromethyl)benzoyl chloride (16.6 mg, 0.088 mmol) were added to 5-((2-amino In a mixture of pyridin-4-yl)oxy)-6-(methoxymethyl)-N-methyl-1H-indole-1-carboxamide (5.5 mg, 0.017 mmol) and tetrahydrofuran (450 μL), And the mixture was stirred for 70 minutes. To the reaction mixture was added tetrahydrofuran, water and ethyl acetate for fractionation. The organic layer was washed with saturated saline solution, and then dried over anhydrous sodium sulfate and filtered with NH silica gel, and the resultant was concentrated under vacuum to obtain a crude product.

The obtained crude product was dissolved in N,N-dimethylformamide (500 μL), 4-hydroxypiperidine (16.5 mg, 0.163 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 12 hours and 50 minutes . Ethyl acetate and water were added to the reaction mixture for fractionation. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel TLC (ethyl acetate) to obtain the title compound (7.6 mg, 83%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.38-1.67 (2H, m), 1.83-1.95 (2H, m), 2.10-2.25 (2H, m), 2.68-2.79 (2H, m), 3.10(3H, d, J=4.8Hz), 3.37(3H, s), 3.56(2H, brs), 3.62-3.77(2H, m), 4.52(2H, s), 5.60-5.69(1H, m) , 6.55 (1H, dd, J = 5.9, 2.2Hz), 6.58 (1H, dd, J = 3.7, 0.7Hz), 7.30 (1H, s), 7.44 (2H, d, J = 8.1Hz), 7.50 ( 1H, d, J = 3.7Hz), 7.82 (2H, d, J = 8.1Hz), 7.97 (1H, d, J = 2.2Hz), 8.09 (1H, d, J = 5.5Hz), 8.21 (1H, s), 8.60 (1H, brs).

The starting material 5-((2-aminopyridin-4-yl)oxy)-6-(methoxymethyl)-N-methyl-1H-indole-1-carboxamide was synthesized by the following method.

[Production Example 140-1]

Benzyl 5-amino-2-(benzyloxy)-4-bromobenzoate

[chemical formula 171]

Benzyl 5-amino-2-(benzyloxy)benzoate (5 g, 15.0 mmol), obtained by benzylation and reduction of commercially available 5-aminosalicylic acid by conventional methods, was dissolved in dichloromethane ( 100 mL) and methanol (50 mL), then tetra-N-butylammoniumtribromide (7.25 g, 15.0 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 4 hours. To the reaction mixture was added aqueous sodium bisulfite and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-3:2). The target fractions were concentrated in vacuo to obtain the title compound (3.58 g, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.88 (2H, s), 5.04 (2H, s), 5.31 (2H, s), 7.15 (1H, s), 7.27-7.43 (11H, m) .

[Production Example 140-2]

Benzyl 5-amino-2-(benzyloxy)-4-((trimethylsilyl)ethynyl)benzoate

[chemical formula 172]

Benzyl 5-amino-2-(benzyloxy)-4-bromobenzoate (3.58 g, 8.68 mmol) described in Production Example 140-1 was dissolved in tetrahydrofuran (20 mL) and triethylamine (40 mL) , then added trimethylsilylacetylene (2.5 mL, 17.7 mmol), bis(triphenylphosphine)palladium(II) chloride (304 mg, 0.434 mmol) and copper(I ) (165mg, 0.868mmol), and the mixture was stirred at 70°C for 6 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum, and the obtained residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=19:1-4:1-7:3 ) for purification. The target fractions were concentrated in vacuo to obtain the title compound (2.75 g, 74%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.25-0.35 (9H, m), 4.03 (2H, s), 5.03 (2H, s), 5.31 (2H, s), 7.00 (1H, s) , 7.20 (1H, s), 7.28-7.47 (10H, m).

[Production example 140-3]

Benzyl 5-(Benzyloxy)-1H-indole-6-carboxylate

[chemical formula 173]

Benzyl 5-amino-2-(benzyloxy)-4-((trimethylsilyl)ethynyl)benzoate (2.75 g, 6.40 mmol) described in Production Example 140-2 was dissolved in N , N-dimethylformamide (30 mL), then copper(I) iodide (610 mg, 3.20 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was heated and stirred at 100° C. for 3 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was filtered with celite. The filtrate was concentrated under vacuum, and the resulting residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=17:3-3:2). The target fractions were concentrated in vacuo to obtain the title compound (1.83 g, 80%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.18 (2H, s), 5.37 (2H, s), 6.44-6.50 (1H, m), 7.22 (1H, s), 7.27-7.38 (7H, m), 7.40-7.46 (2H, m), 7.47-7.53 (2H, m), 7.99 (1H, d, J=0.7Hz), 8.25 (1H, brs).

[Production example 140-4]

(5-(Benzyloxy)-1H-indol-6-yl)methanol

[chemical formula 174]

Lithium aluminum hydride (239 mg, 6.30 mmol) was suspended in tetrahydrofuran (22 mL), and then 5-(benzyloxy)-1H-indole- A solution (1.5 g, 4.20 mmol) of benzyl 6-carboxylate dissolved in tetrahydrofuran (11 mL), and the mixture was stirred at room temperature for 3 hr. Water (0.24 mL), 5M aqueous sodium hydroxide solution (0.24 mL) and water (0.72 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The suspension was filtered through celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo, and the obtained residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1-1:3 ) for purification. The title fractions were concentrated under vacuum to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.95 (1H, t, J = 6.4Hz), 4.81 (2H, d, J = 6.6Hz), 5.17 (2H, s), 6.46-6.50 (1H , m), 7.16-7.21 (2H, m), 7.30-7.43 (4H, m), 7.44-7.50 (2H, m), 8.11 (1H, brs).

[Production example 140-5]

tert-butyl 5-(benzyloxy)-6-(hydroxymethyl)-1H-indole-1-carboxylate

[chemical formula 175]

Under a nitrogen atmosphere at room temperature, tert-butyldimethylsilyl chloride (280 mg, 1.86 mmol) was added to (5-(benzyloxy)-1H-indole-6- (392 mg, 1.55 mmol) and imidazole (158 mg, 2.32 mmol) in N,N-dimethylformamide (3.8 mL), and the mixture was stirred for 70 min. Ethyl acetate and water were added to the reaction mixture for fractionation. The organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under vacuum to obtain a crude product A.

The resulting crude product A was dissolved in dichloromethane (6.0 mL), and di-tert-butyl dicarbonate (538 mg, 2.47 mmol) and 4-dimethylaminopyridine (18.9 mg, 0.155 mmol) were added at room temperature under a nitrogen atmosphere. ), and the mixture was stirred for 1.5 hours. Ethyl acetate and water were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum to obtain a crude product B.

The obtained crude product B was dissolved in tetrahydrofuran (6.0 mL), then 1M tetrabutylammonium fluoride (3.0 mL, 3.00 mmol) was added at room temperature under nitrogen atmosphere, and the mixture was stirred for 6 hr. Ethyl acetate and water were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1). The title fractions were concentrated under vacuum to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.66 (9H, s), 2.42 (1H, t, J = 6.6Hz), 4.82 (2H, d, J = 6.6Hz), 5.17 (2H, s ), 6.49 (1H, dd, J = 3.7, 0.7Hz), 7.09 (1H, s), 7.30-7.49 (5H, m), 7.56 (1H, d, J = 3.7Hz), 8.09 (1H, brs) .

[Production example 140-6]

tert-butyl 5-(benzyloxy)-6-(methoxymethyl)-1H-indole-1-carboxylate

[chemical formula 176]

Methyl iodide (290 μL, 4.66 mmol) and 50%-72% oily sodium hydride (122 mg) were added to 5-(benzyloxy)-6 -(Hydroxymethyl)-1H-indole-1-carboxylic acid tert-butyl ester (547 mg, 1.55 mmol) in a solution of N,N-dimethylformamide (10 mL), and the mixture was stirred for 3 hours 15 minute. The reaction mixture was quenched with water and then diluted with ethyl acetate for fractionation. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum, and the resulting residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1-1:4). The title fractions were concentrated in vacuo to obtain the title compound (487mg, 86%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.67 (9H, s), 3.45 (3H, s), 4.65 (2H, s), 5.14 (2H, s), 6.47 (1H, d, J= 3.7Hz), 7.06 (1H, s), 7.29-7.50 (5H, m), 7.55 (1H, d, J = 3.7Hz), 8.17 (1H, brs).

[Production example 140-7]

6-(methoxymethyl)-1H-indol-5-ol

[chemical formula 177]

At room temperature under nitrogen atmosphere, 28% sodium methoxide (4.0 mL, 19.6 mmol) was added to 5-(benzyloxy)-6-(methoxymethyl)-1H as described in Production Example 140-6 - a solution of tert-butyl indole-1-carboxylate (427 mg, 1.16 mmol) in methanol (4.0 mL), and the mixture was stirred for 2.5 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum to obtain a crude product (301 mg).

The obtained crude product (301 mg) was dissolved in methanol (11 mL), 10% palladium-carbon (water content, 50%) (12.0 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 3 hr. The mixture was diluted with methanol and the catalyst was filtered off through celite. The filtrate was concentrated under vacuum, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:3). The target fractions were concentrated in vacuo to obtain the title compound (156 mg, 76%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.43 (3H, s), 4.73 (2H, s), 6.43-6.47 (1H, m), 6.91 (1H, s), 7.10 (1H, s) , 7.13 (1H, s), 7.17 (1H, t, J=2.7Hz), 8.00 (1H, brs).

According to Examples 1 to 33, the example compounds described in Table 13 (comprising the starting material 5-((2-aminopyridin-4-yl)oxy)-6-(methoxymethyl)-N- Methyl-1H-indole-1-carboxamide) was obtained from 6-(methoxymethyl)-1H-indole-5-ol described in Production Example 140-7 and in Production Example 1-5 Said N-(4-chloropyridin-2-yl)acetamide is synthesized.

[Table 13]

[instance 143]

6-cyano-5-((2-(4-(1-ethylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-N-methyl-1H-indole- 1-formamide

[chemical formula 178]

Add sodium triacetoxyborohydride (10.7 mg, 0.05 mmol) and acetaldehyde (5.6 mg, 0.127 mmol) to 6-cyano-N-methyl-5-((2 -Mixture of (4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (3.9 mg, 7.89 mmol) and tetrahydrofuran (1.0 mL) , and the mixture was stirred for 1 hour. To the reaction mixture was added saturated aqueous sodium bicarbonate and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel TLC (dichloromethane:methanol=49:1) to obtain the title compound (2.54 mg, 62%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.16 (3H, t, J=7.3Hz), 1.81-1.96 (4H, m), 2.06-2.20 (2H, m), 2.47-2.65 (3H, m), 3.01-3.08 (3H, m), 3.16 (2H, d, J = 11.7Hz), 5.82 (1H, brs), 6.59-6.65 (1H, m), 6.76 (1H, dd, J = 5.7, 2.4Hz), 7.33(2H, d, J=8.4Hz), 7.41(1H, s), 7.57(1H, d, J=3.7Hz), 7.78(2H, d, J=8.1Hz), 7.93(1H , s), 8.20 (1H, d, J=5.5Hz), 8.60-8.68 (2H, m).

The starting material 6-cyano-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H- was synthesized by Indole-1-carboxamide.

[Production Example 143-1]

1-(Benzyloxy)-2-chloro-2-nitrobenzene

[chemical formula 179]

Dissolve commercially available 2-chloro-4-nitrophenol (10 g, 57.6 mmol) and benzyl bromide (7.6 mL, 63.9 mmol) in N,N-dimethylformamide (100 mL), and add potassium carbonate (9.56 g, 69.1 mmol), and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The deposited solid was filtered off, washed with methyl tert-butyl ether, and dried by flow drying to obtain the title compound quantitatively.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.28 (2H, s), 7.03 (1H, d, J = 9.2Hz), 7.33-7.48 (5H, m), 8.12 (1H, dd, J = 9.2, 2.9 Hz), 8.32 (1H, d, J = 2.6 Hz).

[Production Example 143-2]

2-(5-(Benzyloxy)-4-chloro-2-nitrophenyl)acetonitrile

[chemical formula 180]

1-(Benzyloxy)-2-chloro-4-nitrobenzene (5 g, 19.0 mmol) and 4-chlorophenoxyacetonitrile (3.50 g, 20.9 mmol) described in Production Example 143-1 were dissolved in N,N-Dimethylformamide (35 mL), and then potassium tert-butoxide (2 g, 17.8 mmol) was added at -30°C to -40°C under nitrogen atmosphere. Potassium tert-butoxide (2.32 g, 20.7 mmol) was added at the same temperature. The mixture was stirred at the same temperature for 45 minutes, and then 1M hydrochloric acid was added. After extraction with ethyl acetate, the organic layer was washed twice with water and with a saturated saline solution, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under vacuum, the resulting residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:1 -1:1) for purification. Fractions of the mixture were concentrated under vacuum, the resulting residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1-13:7) Purify. The resulting solid was washed with diethyl ether to obtain the title compound (1.04 g, 18%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.24 (2H, s), 5.33 (2H, s), 7.29 (1H, s), 7.34-7.52 (5H, m), 8.34 (1H, s) .

[Production Example 143-3]

6-Chloro-1H-indol-5-ol

[chemical formula 181]

2-(5-(Benzyloxy)-4-chloro-2-nitrophenyl)acetonitrile (1.04 g, 3.45 mmol) described in Production Example 143-2 was suspended in ethanol (40 mL) and stirred at room temperature 5% rhodium-carbon (355 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere for 39 hours and 20 minutes. Methanol was added to the reaction mixture, and the resulting mixture was filtered with celite. The filtrate was concentrated under vacuum, and the resulting solid was filtered off and washed with ethyl acetate. The filtrate was concentrated, the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2), and the target fraction was concentrated under vacuum to obtain a crude product.

The obtained crude product was dissolved in ethanol (20 mL), 10% palladium-carbon (water content, 50%) (367 mg) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere for 50 minutes. Methanol was added to the reaction mixture, and the resulting mixture was filtered with celite. The filtrate was concentrated under vacuum and the resulting solid was filtered off and washed with dichloromethane. The filtrate was concentrated, the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1-3:2), and the target fraction was concentrated in vacuo to obtain the title compound (193 mg, 33 %).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.25 (1H, s), 6.41-6.47 (1H, m), 7.19 (1H, t, J=2.7Hz), 7.24 (1H, s), 7.37 (1H, s), 8.02 (1H, brs).

[Production example 143-4]

5-((2-aminopyridin-4-yl)oxy)-1H-indole-6-carbonitrile

[chemical formula 182]

6-Chloro-1H-indol-5-ol (137 mg, 0.817 mmol) described in Production Example 143-3 was dissolved in dimethylsulfoxide (1.0 mL), and Production Example was added at room temperature under nitrogen atmosphere N-(4-chloropyridin-2-yl)acetamide (181 mg, 1.06 mmol) and potassium tert-butoxide (110 mg, 0.981 mmol) described in 1-5, and the mixture was heated and stirred at 150° C. 6.5 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under vacuum, and the resulting residue was dissolved in dichloromethane, and the resultant was subjected to NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:3-0: 1) Purify. The target fractions were concentrated under vacuum to obtain a crude product A (96.6 mg).

A part (57.4 mg) of the obtained crude product A was dissolved in methanol (2 mL), 2M sodium hydroxide solution (2 mL) was added at room temperature under nitrogen atmosphere, and the mixture was heated and stirred at 65° C. for 2 hr. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum, and the resulting residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1). The target fractions were concentrated under vacuum to obtain a crude product B (34.7 mg).

A portion (10.4 mg) of the obtained crude product B, bis(tri-tert-butylphosphine)palladium(0) (8.19 mg, 0.016 mmol) and zinc cyanide (9.4 mg, 0.08 mmol) were dissolved in N,N-di methylacetamide (500 μL), and the mixture was heated and stirred at 150° C. for 1 hour under nitrogen atmosphere and microwave irradiation. Ethyl acetate and water were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by silica gel TLC (n-heptane:ethyl acetate=1:3) to obtain the title compound (5.0 mg, 14%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.57 (2H, brs), 5.97 (1H, d, J=2.2Hz), 6.31 (1H, dd, J=6.2, 2.2Hz), 6.56-6.63 (1H, m), 7.41(1H, s), 7.48(1H, t, J=3.0Hz), 7.77(1H, s), 7.92(1H, d, J=5.9Hz), 8.98(1H, brs) .

According to Examples 1 to 33, the example compounds described in Table 14 (comprising the starting material 6-cyano-N-methyl-5-((2-(4-(piperidin-4-yl)benzyl) from Example 143 Amide) pyridin-4-yl) oxy)-1H-indole-1-carboxamide) was obtained from 5-((2-aminopyridin-4-yl) oxy) described in production example 143-5 -1H-indole-6-carbonitrile synthesized.

[Table 14]

[Instance 145]

6-(Dimethylamino)-N-methyl-5-((2-(4-(1-methylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H -Indole-1-carboxamide

[chemical formula 183]

36.5% aqueous formaldehyde (7.95 μL, 0.105 mmol), sodium triacetoxyborohydride (14 mg, 0.066 mmol) and acetic acid (3.02 μL, 0.053 mmol) were added to 6-(dimethylamino)- N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-1H-indole-1-carboxamide (5.4mg, 10.5 μmol) and tetrahydrofuran (300 μL), and the mixture was stirred for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and ethyl acetate for fractionation. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the obtained residue was dissolved in chloroform, and the resultant was purified by NH silica gel TLC (ethyl acetate). The resulting solid was washed with diethyl ether to obtain the title compound (3.31 mg, 60%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.77-1.88 (4H, m), 2.01-2.11 (2H, m), 2.33 (3H, s), 2.48-2.60 (1H, m), 2.79 ( 6H, s), 2.95-3.03(2H, m), 3.07(3H, d, J=4.8Hz), 5.48(1H, brs), 6.47(1H, dd, J=5.9, 2.6Hz), 6.52(1H , d, J=3.7Hz), 7.22-7.25(2H, m), 7.33(2H, d, J=8.4Hz), 7.78-7.84(2H, m), 7.96(1H, s), 7.99(1H, d, J = 2.2 Hz), 8.06 (1H, d, J = 5.9 Hz), 8.49 (1H, brs).

The starting material 6-(dimethylamino)-N-methyl-5-((2-(4-(piperidin-4-yl)benzamide)pyridin-4-yl)oxy) was synthesized by -1H-indole-1-carboxamide.

[Production Example 145-1]

4-(Benzyloxy)-3-nitroaniline

[chemical formula 184]

Commercially available 4-amino-2-nitrophenol (5 g, 32.4 mmol) and triphenylphosphine (10.2 g, 38.9 mmol) were dissolved in dichloromethane (200 mL), and benzyl alcohol was added at 0 °C (4.0 mL, 38.7 mmol), then a solution of diisopropyl azodicarboxylate (7.87 g, 38.9 mmol) in dichloromethane (50 mL) was added, and the mixture was stirred at room temperature for 21.5 hours. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:3) , and the target fraction was concentrated under vacuum to obtain the title compound (7.26 g, 92%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.09 (2H, s), 5.25 (2H, s), 6.81 (1H, dd, J=9.0, 2.7Hz), 7.01 (1H, d, J = 2.9 Hz), 7.13 (1H, d, J = 9.2 Hz), 7.25-7.44 (5H, m).

[Production Example 145-2]

4-(Benzyloxy)-2-bromo-5-nitroaniline

[chemical formula 185]

4-(Benzyloxy)-3-nitroaniline (2.9 g, 11.9 mmol) described in Production Example 145-1 was dissolved in dichloromethane (80 mL) and methanol (40 mL), and then at room temperature in Tetra-N-butylammonium tribromide (5.73 g, 11.9 mmol) was added under nitrogen atmosphere, and the mixture was stirred for 50 minutes. The reaction mixture was diluted with an aqueous sodium bisulfite solution and dichloromethane. The organic layer was washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under vacuum, and the resulting residue was dissolved in dichloromethane, and the resultant was subjected to silica gel column chromatography (n-heptane:ethyl acetate=9:1-3: 2) Purify. The title fractions were concentrated in vacuo to obtain the title compound (2.59 g, 67%) in 84% purity.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.06 (2H, brs), 5.12 (2H, s), 7.25 (1H, s), 7.31 (1H, s), 7.32-7.47 (5H, m) .

[Production Example 145-3]

4-(Benzyloxy)-5-nitro-2-((trimethylsilyl)ethynyl)aniline

[chemical formula 186]

4-(Benzyloxy)-2-bromo-5-nitroaniline (2.59 g, 8.01 mmol) described in Production Example 145-2 was dissolved in tetrahydrofuran (20 mL) and triethylamine (40 mL), then Trimethylsilylacetylene (2.26 mL, 16.0 mmol), bis(triphenylphosphine)palladium(II) chloride (291 mg, 0.415 mmol) and copper(I) iodide (164 mg, 0.861 mmol) were added at room temperature ), and the mixture was heated and stirred at 60° C. under a nitrogen atmosphere for 6 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:1). The target fractions were concentrated under vacuum to obtain the title compound (2.19 g, 80%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.28 (9H, s), 4.19 (2H, brs), 5.11 (2H, s), 7.09 (1H, s), 7.21 (1H, s), 7.29 -7.48 (5H, m).

[Production Example 145-4] 5-(Benzyloxy)-6-nitro-1H-indole

[chemical formula 187]

4-(Benzyloxy)-5-nitro-2-(trimethylsilyl)ethynyl)aniline (2.19 g, 6.44 mmol) described in Production Example 145-3 was dissolved in N,N- To dimethylformamide (20 mL), copper(I) iodide (1.23 g, 6.44 mmol) was added at room temperature, and the mixture was heated and stirred at 100°C. Water and ethyl acetate were added to the reaction mixture for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-7:3-3:2). The target fractions were concentrated in vacuo to obtain the title compound (1.23 g, 71%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.24 (2H, s), 6.49-6.56 (1H, m), 7.27-7.46 (5H, m), 7.49-7.57 (2H, m), 8.06 ( 1H, d, J = 1.1 Hz), 8.39 (1H, brs).

[Production example 145-5]

6-Amino-1H-indol-5-ol

[chemical formula 188]

5-(Benzyloxy)-6-nitro-1H-indole (400 mg, 1.49 mmol) described in Production Example 145-4 was suspended in methanol (10 mL) and tetrahydrofuran (5 mL), and added at room temperature 10% palladium-carbon (water content, 50%) (159 mg), and the mixture was stirred under a hydrogen atmosphere for 50 minutes. Methanol was added to the reaction mixture, and the resulting mixture was filtered with celite. The filtrate was concentrated under vacuum, and the resulting solid was washed with diethyl ether and ethyl acetate to obtain the title compound (168 mg, 76%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.31 (2H, brs), 6.05 (1H, t, J=2.0Hz), 6.59 (1H, s), 6.74 (1H, s), 6.88 (1H,t,J=2.8Hz), 8.48(1H,brs), 10.25(1H,brs).

[Production example 145-6]

6-(Dimethylamino)-1H-indol-5-ol

[chemical formula 189]

6-Amino-1H-indol-5-ol (80 mg, 0.54 mmol) described in Production Example 145-5 was dissolved in tetrahydrofuran (5.4 mL), and 36.5% aqueous formaldehyde (122 μL, 1.62 mmol) was added at room temperature , sodium triacetoxyborohydride (343 mg, 1.62 mmol) and acetic acid (93 μL, 1.62 mmol), and the mixture was stirred for 2 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, and the obtained residue was dissolved in dichloromethane, and the resultant was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=7:3-1:4). The target fractions were concentrated in vacuo to obtain the title compound (62.0 mg, 65%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.70 (6H, s), 6.42 (1H, ddd, J=3.0, 2.1, 1.1Hz), 7.11-7.15 (2H, m), 7.21 (1H, s), 7.94 (1H, brs).

According to Examples 1 to 33, the example compounds illustrated in Table 15 (comprising the starting material 6-(dimethylamino)-N-methyl-5-((2-(4-(piperidine-4- Base) benzamide) pyridin-4-yl) oxy)-1H-indole-1-carboxamide) was obtained from 6-(dimethylamino)-1H-indole as described in Production Example 145-6 Indol-5-ol and N-(4-chloropyridin-2-yl)acetamide described in Production Examples 1-5.

[Table 15]

[instance 148]

5-((2-(4-(1-(2-hydroxyethyl)-2-oxopyridin-4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methyl Oxyethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 190]

5-((2-aminopyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole- 1-Carboxamide (460 mg, 1.29 mmol), 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2- as described in Production Example 148-4 Oxopyridin-4-yl)benzoic acid (585 mg, 1.55 mmol) and 4-dimethylaminopyridine (315 mg, 2.58 mmol) were dissolved in 1,2-dimethoxyethane (6 mL), and triethyl Amine (360 μL, 2.58 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (495 mg, 2.58 mmol), and the mixture was stirred at room temperature for 1 hour and then Stir at 55°C for 2 hours. To the reaction mixture was added 2M hydrochloric acid (5 L, 10.0 mmol), and the mixture was stirred for 3 hrs. Ethyl acetate was added to the reaction mixture, the resultant was neutralized with 2M sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and then the organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=24:1-9:1). The target fractions were concentrated under vacuum, then a solid was precipitated by using dichloromethane and methyl tert-butyl ether, and the solid was filtered off to obtain the title compound (632 mg, 81%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.98-2.10 (1H, m), 2.11-2.22 (1H, m), 2.54 (1H, dd, J=17.6, 11.0Hz), 2.71-2.81 ( 1H, m), 3.06(3H, d, J=4.4Hz), 3.15-3.23(2H, m), 3.26(3H, s), 3.39-3.48(1H, m), 3.49-3.61(4H, m) , 3.63-3.71(1H, m), 3.84(2H, d, J=4.8Hz), 4.08-4.26(2H, m), 5.60(1H, brs), 6.55(1H, d, J=3.3Hz), 6.62 (1H, dd, J = 5.7, 2.4Hz), 7.26-7.35 (4H, m), 7.85 (2H, d, J = 8.4Hz), 7.91 (1H, d, J = 2.2Hz), 8.02 (1H , s), 8.09 (1H, d, J = 5.9 Hz), 8.56 (1H, brs).

The starting material 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxopiperidin-4-yl)benzoic acid was synthesized by the following method.

[Production Example 148-1]

tert-butyl 4-(4-(benzyloxy)carbonyl)phenyl)piperidine-1-carboxylate

[chemical formula 191]

4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (3.0 g, 9.82 mmol) described in Production Examples 1-12 was dissolved in N,N-dimethylformamide ( 15 mL), potassium carbonate (1.63 g, 11.8 mmol) and benzyl bromide (1.29 mL, 10.8 mmol) were then added, and the mixture was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction mixture for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1). The target fractions were concentrated under vacuum to obtain the title compound (3.83 g, 99%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.48 (9H, s), 1.58-1.70 (2H, m), 1.82 (2H, d, J=12.4Hz), 2.56-2.96 (3H, m) , 4.17-4.39 (2H, m), 5.36 (2H, s), 7.25-7.29 (3H, m), 7.31-7.50 (4H, m), 8.02 (2H, d, J=8.4Hz).

[Production Example 148-2]

Benzyl 4-(2-oxopiperidin-4-yl)benzoate

[chemical formula 192]

tert-Butyl 4-(4-((benzyloxy)carbonyl)phenyl)piperidine-1-carboxylate (3.83 g, 9.68 mmol) as described in Production Example 148-1 was dissolved in ethyl acetate (90 mL) , then Ruthenium(IV) oxide hydrate (44.0 mg, 0.29 mmol) and sodium periodate (8.29 g, 38.7 mmol) dissolved in water (270 mL) were added at room temperature, and the mixture was stirred at room temperature for 18 Hour. Ethyl acetate was added to the reaction mixture for fractionation, and then the organic layer was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, the resulting residue was dissolved in dichloromethane (30 mL), then trifluoroacetic acid (15 mL, 202 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The resultant was concentrated in vacuo, and to the residue was added a saturated aqueous sodium carbonate solution. Ethyl acetate was added for fractionation, and then the organic layer was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, and the residue was washed with diethyl ether to obtain the title compound (2.03 g, 68%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.88-2.05 (1H, m), 2.06-2.17 (1H, m), 2.41-2.58 (1H, m), 2.64-2.78 (1H, m), 3.10-3.26(1H, m), 3.33-3.52(2H, m), 5.37(2H, s), 5.71-5.83(1H, m), 7.27-7.50(7H, m), 8.01-8.10(2H, m ).

[Production Example 148-3]

Benzyl 4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxopiperidin-4-yl)benzoate

[chemical formula 193]

Benzyl 4-(2-oxopiperidin-4-yl)benzoate (1.3 g, 4.20 mmol) described in Production Example 148-2 was dissolved in dimethylsulfoxide (20 mL), and then 50%-72% oily sodium hydride (218 mg) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hr. Subsequently, tert-butyl(2-iodoethoxy)dimethylsilane (1.92 g, 6.27 mmol) dissolved in dimethylsulfoxide (10 mL) was added and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added saturated aqueous ammonium chloride and ethyl acetate at 0°C for fractionation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=10:1-1:2). The target fractions were concentrated in vacuo to obtain the title compound (920 mg, 47%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.06 (6H, d, J=1.8Hz), 0.89 (9H, s), 1.87-2.03 (1H, m), 2.07-2.18 (1H, m) , 2.50 (1H, dd, J = 17.4, 11.2Hz), 2.63-2.81 (1H, m), 3.09-3.20 (1H, m), 3.46-3.59 (4H, m), 3.82 (2H, t, J = 5.3Hz), 5.36 (2H, s), 7.27-7.50 (7H, m), 8.01-8.08 (2H, m).

[Production example 148-4]

4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxopiperidin-4-yl)benzoic acid

[chemical formula 194]

4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxopyridin-4-yl)benzoic acid described in Example 148-3 will be produced Benzyl ester (920 mg, 1.97 mmol) was dissolved in methanol (20 mL), then 10% palladium-carbon (water content, 50%) (209 mg) was added, and the mixture was stirred under hydrogen atmosphere for 3 hr. The inside of the reaction system was substituted with nitrogen, then the catalyst was filtered off with celite, and the resultant was washed with methanol. The filtrate was concentrated under vacuum, and the resultant was purified by silica gel column chromatography (n-heptane:ethyl acetate=2:1-0:1). The target fractions were concentrated in vacuo to obtain the title compound (592 mg, 80%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.07 (6H, d, J=1.5Hz), 0.90 (9H, s), 1.96-2.02 (1H, m), 2.10-2.16 (1H, m) , 2.52 (1H, dd, J = 17.6, 11.0Hz), 2.72-2.80 (1H, m), 3.10-3.24 (1H, m), 3.47-3.60 (4H, m), 3.83 (2H, t, J = 5.5 Hz), 7.31 (2H, d, J = 8.1 Hz), 8.06 (2H, d, J = 8.4 Hz).

According to Examples 1 to 33, the example compounds illustrated in Table 16 were obtained from 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy) as described in Production Example 24-8 Oxy)-N-methyl-1H-indole-1-carboxamide was synthesized.

[Table 16]

[Instance 150]

5-((2-(((4-(cis-1-(2-hydroxyethyl)-1-oxypiperidin-4-yl)phenyl)carbonyl)amino)pyridin-4-yl)oxy )-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 195]

3-Chloroperoxybenzoic acid (229 mg, 0.864 mmol) (purity: 65%) was added to 5-((2-(4-(1-(2-hydroxyethyl Base) piperidin-4-yl) benzamide) pyridin-4-yl) oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide (508 mg, 0.864 mmol) and dichloromethane (25 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added ethyl acetate and 10% aqueous sodium sulfite for fractionation. The aqueous layer was saturated with sodium chloride, and extracted by using a mixed solvent of ethyl acetate, tetrahydrofuran and methanol. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the resulting residue was dissolved in methanol and dichloromethane, and the resultant was purified by NH silica gel column chromatography (chloroform:methanol=49:1-4:1). The target fraction was concentrated under vacuum, and the precipitated solid was then dissolved in ethyl acetate, tetrahydrofuran and methanol. The precipitated solid was filtered off and washed with ethyl acetate to obtain a filtrate. The filtrate was concentrated under vacuum (168 mg), suspended in tetrahydrofuran, ethyl acetate and isopropanol, and the resultant was stirred at 60°C for 20 minutes. The resultant was cooled to room temperature, and the precipitated solid was filtered off and washed with ethyl acetate to obtain a filtrate. The filtrate was concentrated in vacuo (62.4 mg), and a part (10.4 mg) of the filtrate was purified by ODS column chromatography (0.5% trifluoroacetic acid/water:acetonitrile=37:13) to separate it into one One cis-form (retention time = 73-75 min) and one trans-form (retention time = 65-67 min). A buffer was added thereto, and after extraction with butanol, these solvents were concentrated under vacuum, and the resultant was subjected to ODS column chromatography (methanol:water=1:9, acetonitrile:water=1:9, Purification with acetonitrile followed by methanol) afforded the cis-form of the title compound (1.1 mg) as a highly polar component and the less polar component of Example 151.

cis-form

¹ H-NMR spectrum (600 MHz, DMSO-d ₆ ) δ (ppm): 1.68 (2H, d, J = 13.0 Hz), 2.32-2.63 (2H, m), 2.72-2.81 (1H, m), 2.85 ( 3H, d, J = 4.2Hz), 3.06-3.56 (11H, m), 3.86-3.97 (2H, m), 4.03-4.14 (2H, m), 6.63 (1H, d, J = 3.5Hz), 6.67 (1H, dd, J=5.7, 2.4Hz), 7.37(2H, d, J=8.2Hz), 7.45(1H, s), 7.64-7.72(1H, m), 7.75-7.82(1H, m), 7.93 (2H, d, J=8.2Hz), 8.08 (1H, s), 8.11-8.24 (2H, m), 10.65 (1H, s).

[instance 151]

5-((2-(((4-(trans-1-(2-hydroxyethyl)-1-oxypiperidin-4-yl)phenyl)carbonyl)amino)pyridin-4-yl)oxy )-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide

[chemical formula 196]

The trans-form of the less polar component of Example 150 was obtained (1.3 mg).

trans-form

¹ H-NMR spectrum (600MHz, DMSO-d ₆ ) δ (ppm): 1.85-2.03 (4H, m), 2.85 (3H, d, J=4.2Hz), 2.90-3.02 (1H, m), 3.05- 3.63(11H, m), 3.72-3.91(2H, m), 3.99-4.18(2H, m), 6.63(1H, d, J=3.5Hz), 6.68(1H, dd, J=5.8, 2.1Hz) , 7.34-7.53 (3H, m), 7.68 (1H, d, J = 2.1Hz), 7.78 (1H, d, J = 3.5Hz), 7.92 (2H, d, J = 8.2Hz), 8.08 (1H, s), 8.12-8.25 (2H, m), 10.65 (1H, s).

[instance 152]

6-(2-hydroxyethoxy)-5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy) -N-Methyl-1H-indole-1-carboxamide

[chemical formula 197]

Boron tribromide (2.55 mL, 2.55 mmol) was added to 5-((2-(4-(1-(2-hydroxyethyl)piperidine) as described in Example 22 at 0°C under nitrogen atmosphere -4-yl)benzamide)pyridin-4-yl)oxy)-6-(2-methoxyethoxy)-N-methyl-1H-indole-1-carboxamide (500mg, 0.851 mmol) and dichloromethane (5 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled to 0 °C, and then methanol and a saturated aqueous sodium bicarbonate solution were added for fractionation. The aqueous layer was extracted with dichloromethane, then the organic layers were combined, and the resultant was washed with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0-5:1). The target fractions were concentrated under vacuum, and the resulting solid was washed with dichloromethane to obtain the title compound (97 mg, 20%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.58-1.79 (4H, m), 2.00-2.11 (2H, m), 2.41 (2H, t, J=6.4Hz), 2.52-2.59 ( 1H, m), 2.85(3H, d, J=4.4Hz), 2.97(2H, d, J=11.7Hz), 3.46-3.58(4H, m), 3.96-4.01(2H, m), 4.37(1H , t, J=5.3Hz), 4.72(1H, t, J=5.5Hz), 6.63(1H, d, J=3.5Hz), 6.66(1H, m), 7.33(2H, m), 7.43(1H , s), 7.70 (1H, d, J = 2.2Hz), 7.78 (1H, d, J = 3.7Hz), 7.85-7.96 (2H, m), 8.10 (1H, s), 8.13-8.26 (2H, m), 10.65 (1H, brs).

The mass spectra (ESI-MS (m/z)) of these compounds of Examples 34 to 130, Example 132, Example 134, Examples 136 to 139, Example 141, Example 142, Example 144, Example 146, Example 147 and Example 149 were obtained at Described in Tables 17 and 18.

[Table 17]

[Table 18]

[Pharmacological test example]

1. FGFR1 Kinase Assay

In this assay, the inhibitory activity of a test substance on the tyrosine kinase activity of the FGFR1 protein is measured.

To each well of a flat-bottomed 96-well white plate (Sumitomo Bakelite Co., Ltd. (Sumitomo Bakelite Co., Ltd.), MS-8496W), an assay buffer (20 mM HEPES-NaOH, 0.01% Triton X-100 , 2mMDTT, and 5mM MgCl ₂ ) diluted to 1 μg/mL of a solution of 10 μl of a FGFR1 protein (Carna Biosciences, Inc., 08-133), containing a final concentration of 1000 nM CSK-tide substrate (Ana Spec Inc., 63843) and 58.3 μM final concentration of ATP (Promega Corporation (US Promega company), V9102) of 10 μL of an assay buffer solution, and 5 μl of a test substance diluted with the assay buffer, and at room temperature The reaction was carried out for 1 hour. To measure kinase activity, the ADP-Glo(TM) kinase assay (Promega Corporation, V9102) was used. After the reaction, 25 μL of ADP-Glo reagent was added to each well of the plate and the reaction was carried out at room temperature for 40 minutes to stop the kinase reaction and deplete the remaining ATP. Kinase detection reagent was additionally added and the reaction was carried out at room temperature for 40 minutes to induce conversion of ADP to ATP, luciferase/luciferin coupling reaction and luminescence reaction by ATP. The amount of luminescence in each well was measured by Envision(TM) (PerkinElmer Co., Ltd. (PerkinElmer Co., Ltd.)) for evaluation of the enzyme activity. Assuming that the amount of luminescence obtained by adding the kinase protein without adding the test substance is 100% and that the amount of luminescence obtained by adding neither the test substance nor the kinase protein is 0%, obtain the luminescence in the presence of the test substance volume ratio. On the basis of this luminescent amount ratio, the concentration of the test substance required to inhibit the kinase activity by 50% (i.e., the IC ₅₀ value) was calculated, and the respective test substances thus calculated are shown in Tables 19, 20 and 21 _IC50 values.

<Data on FGFR1 Cell-Free Kinase Inhibition>

[Table 19]

[Table 20]

[Table 21]

2. FGFR2 Kinase Assay

In this assay, the inhibitory activity of a test substance on the tyrosine kinase activity of the FGFR2 protein is measured.

To each well of a flat-bottomed 96-well white plate (Sumitomo Bakelite Co., Ltd. (Sumitomo Bakelite Co., Ltd.), MS-8496W), an assay buffer (20 mM HEPES-NaOH, 0.01% Triton X-100 , 2mMDTT, and 5mM MgCl ₂ ) diluted to 1 μg/mL of a solution of 10 μl of a FGFR2 protein (Carna Biosciences, Inc., 08-134), containing a final concentration of 1000 nM CSK-tide substrate (Ana Spec Inc., 63843) and 10 μL of an assay buffer solution of 35 μM final concentration of ATP (Promega Corporation, V9102), and 5 μl of a test substance diluted with the assay buffer, and at room temperature The reaction was carried out for 1 hour. To measure kinase activity, the ADP-Glo(TM) kinase assay (Promega Corporation, V9102) was used. After the reaction, 25 μL of ADP-Glo reagent was added to each well of the plate and the reaction was carried out at room temperature for 40 minutes to stop the kinase reaction and deplete the remaining ATP. Kinase detection reagent was additionally added and the reaction was carried out at room temperature for 40 minutes to induce conversion of ADP to ATP, luciferase/luciferin coupling reaction and luminescence reaction by ATP. The amount of luminescence in each well was measured by Envision(TM) (PerkinElmer Co., Ltd. (PerkinElmer Co., Ltd.)) for evaluation of the enzyme activity. Assuming that the amount of luminescence obtained by adding the kinase protein without adding the test substance is 100% and that the amount of luminescence obtained by adding neither the test substance nor the kinase protein is 0%, obtain the luminescence in the presence of the test substance volume ratio. On the basis of this luminescent amount ratio, the concentration of the test substance required to inhibit the kinase activity by 50% (i.e., the IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance was shown in Table 22 .

<Data on FGFR2 Cell-Free Kinase Inhibition>

[Table 22]

3. FGFR3 Kinase Assay

In this assay, the inhibitory activity of a test substance on the tyrosine kinase activity of the FGFR3 protein is measured.

To each well of a flat-bottomed 96-well white plate (Sumitomo Bakelite Co., Ltd. (Sumitomo Bakelite Co., Ltd.), MS-8496W), an assay buffer (20 mM HEPES-NaOH, 0.01% Triton X-100 , 2mMDTT, and 5mM MgCl ₂ ) diluted to 1 μg/mL of a solution of 10 μl of a FGFR3 protein (Carna Biosciences, Inc., 08-135), containing a final concentration of 1000 nM CSK-tide substrate (Ana Spec Inc., 63843) and 10 μL of an assay buffer solution of 16.7 μM final concentration of ATP (Promega Corporation (U.S. Promega, V9102), and 5 μl of a test substance diluted with the assay buffer, and at room temperature The reaction was carried out for 2 hours. To measure kinase activity, the ADP-Glo(TM) kinase assay (Promega Corporation, V9102) was used. After the reaction, 25 μL of ADP-Glo reagent was added to each well of the plate and the reaction was carried out at room temperature for 40 minutes to stop the kinase reaction and deplete the remaining ATP. Kinase detection reagent was additionally added and the reaction was carried out at room temperature for 40 minutes to induce conversion of ADP to ATP, luciferase/luciferin coupling reaction and luminescence reaction by ATP. The amount of luminescence in each well was measured by Envision(TM) (PerkinElmer Co., Ltd. (PerkinElmer Co., Ltd.)) for evaluation of the enzyme activity. Assuming that the amount of luminescence obtained by adding the kinase protein without adding the test substance is 100% and that the amount of luminescence obtained by adding neither the test substance nor the kinase protein is 0%, obtain the luminescence in the presence of the test substance volume ratio. On the basis of this luminescent amount ratio, the concentration of the test substance required to inhibit the kinase activity by 50% (i.e., the IC ₅₀ value) was calculated, and the IC ₅₀ value of each test substance thus calculated was shown in Table 23 .

<Data on FGFR3 Cell-Free Kinase Inhibition>

[Table 23]

4. FGFR4 Kinase Assay

In this assay, the inhibitory activity of a test substance on the tyrosine kinase activity of the FGFR4 protein is measured.

To each well of a flat-bottomed 96-well white plate (Sumitomo Bakelite Co., Ltd. (Sumitomo Bakelite Co., Ltd.), MS-8496W), an assay buffer (20 mM HEPES-NaOH, 0.01% Triton X-100 , 2mMDTT, 5mM MgCl ₂ and 2mM MnCl ₂ ) diluted to 1 μg/mL of 10 μl of a FGFR4 protein (CarnaBiosciences, Inc., 08-136) solution, containing a final concentration of 1000nM CSK-tide substrate (Ana Spec Inc ., 63843) and 10 μL of an assay buffer solution of 75 μM final concentration of ATP (Promega Corporation (US Promega Corporation), V9102), and a test substance of 5 μl diluted with the assay buffer, and in The reaction was carried out at room temperature for 2 hours. To measure kinase activity, the ADP-Glo(TM) kinase assay (Promega Corporation, V9102) was used. After the reaction, 25 μL of ADP-Glo reagent was added to each well of the plate and the reaction was carried out at room temperature for 40 minutes to stop the kinase reaction and deplete the remaining ATP. Kinase detection reagent was additionally added and the reaction was carried out at room temperature for 40 minutes to induce conversion of ADP to ATP, luciferase/luciferin coupling reaction and luminescence reaction by ATP. The amount of luminescence in each well was measured by Envision(TM) (PerkinElmer Co., Ltd. (PerkinElmer Co., Ltd.)) for evaluation of the enzyme activity. Assuming that the amount of luminescence obtained by adding the kinase protein without adding the test substance is 100% and that the amount of luminescence obtained by adding neither the test substance nor the kinase protein is 0%, obtain the luminescence in the presence of the test substance volume ratio. On the basis of this luminescent amount ratio, the concentration of the test substance required to inhibit the kinase activity by 50% (i.e., the _IC50 value) was calculated, and the thus calculated _IC50 value of each test substance was shown in Table 24 .

<Data on FGFR4 Cell-Free Kinase Inhibition>

[Table 24]

5. SNU-16 Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance is measured in a human gastric cancer cell line with FGFR2 gene amplification.

It has been reported that the human gastric cancer cell line SNU-16 (ATCC number CRL-5974) contains FGFR2 gene amplification (Cancer Res. ("Cancer Research") 2008.68: 2340-2348). By using RPMI-1640 (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.), 168-23191) containing 10% FBS and penicillin/streptomycin (Wako Pure Pharmaceutical Industry Co., Ltd., 187-02021) medium, SNU-16 cells were maintained in a 5% CO ₂ incubator (37°C). To each well of a 96-well plate (Becton, Dickinson and Company (Becton, USA), 35-3075), add 150 μL of RPMI-1640 medium containing 10% FBS to a concentration of 1 x 10 ⁴ cells /mL of SNU-16 cell suspension, and the resultant was cultured overnight in a 5% CO ₂ incubator (37°C). On the next day, 50 μL of a test substance diluted with RPMI-1640 medium containing 10% FBS was added to each well, and the resultant was cultured in a 5% CO ₂ incubator (37° C.) for 3 days. 10 μL of Cell Counting Kit-8 (Dojindo Laboratories, CK04) was added to each well, and the resultant was cultured in a 5% _CO incubator (37° C.) for 1 to 2 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd.) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained without the addition of the test substance is 100% and the absorbance obtained in wells containing no cells is 0%, the absorbance ratio in the presence of the test substance is obtained. The concentration of the test substance required to inhibit the cell growth by 50% (ie the IC ₅₀ value) was calculated, and the IC ₅₀ values thus calculated for the respective test substances are shown in Tables 25, 26 and 27.

<Evaluation data of growth inhibitory effect of SNU-16>

[Table 25]

[Table 26]

[Table 27]

6. HUVEC Growth Inhibition Assay

In this assay, the inhibitory activity of a test substance on the growth of vascular endothelial cells induced by VEGF is measured.

Normal Human umbilical vein endothelial cells (HUVEC) were isolated. In a 5% _CO incubator (37° C.), these cells were cultured by using EGM-2 medium (LONZA Inc. (Lonza Company), CC-3162) To confluency. To each well of a 96-well plate (Becton, Dickinson and Company (BD company), 35-3075), add 100 μL of HUVEC cell suspension (which has been prepared by using 2% fetal bovine serum (FBS: Cell Culture Technologies) (Cell Culture Technology Inc., CC3008-504) of EGM-2 medium was adjusted to a concentration of 1.5 x 10 ⁴ cells/mL), and the resultant was cultured overnight in a 5% CO ₂ incubator (37° C.). The next day, a test substance diluted with EGM-2 medium containing 2% FBS, and 50 μL of VEGF (R&D Systems, 293-VE-010) (which had been prepared by using EGM-2 medium adjusted to a final concentration of 10 ng/mL), and the resultant was cultured for 3 days in a 5% CO ₂ incubator (37° C.). Add 20 μL of cell counting kit (Cell CountingKit)-8 (Dojindo Laboratories (Dojindo Institute of Chemistry), CK04), and the resultant was incubated in a 5% _CO incubator (37° C.) for 3 to 4 hours to cause a color reaction. Using ENVISION (TM) (PerkinElmer Co., Ltd. (PerkinElmer Co., Ltd.)) was used to measure the absorbance at 450nm.Assuming that the absorbance obtained without adding the test substance but having VEGF was 100% and that the test substance was not added The absorbance obtained without adding VEGF was 0%, and the absorbance ratio in the presence of the test substance was obtained. On the basis of the absorbance ratio, the amount of the test substance required for 50% inhibition of HUVEC growth in the presence of VEGF was calculated. Concentrations (ie IC ₅₀ values) and the IC ₅₀ values calculated therefrom for each test substance are shown in Tables 28, 29 and 30.

<Evaluation data of HUVEC growth inhibitory effect>

[Table 28]

[Table 29]

[Table 30]

7. NCI-H1581 Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance is measured in a human lung cancer cell line with amplification of the FGFR1 gene.

Human lung cancer cell line NCI-H1581 (ATCC number CRL-5878) has been reported to have FGFR1 gene amplification (PLoS One ("Public Library of Science Comprehensive"), 2011; 6:e20351, Sci Transl Med ("Science Transformation Medicine") 2010;2:62ra93). NCI-H1581 cells were maintained in a 5% CO ₂ incubator (37° C.) by using RPMI-1640 medium containing 10% FBS and penicillin/streptomycin. To each well of a 96-well plate (Becton, Dickinson and Company (Becton, USA), 35-3075), add 150 μL of RPMI-1640 medium containing 10% FBS to a concentration of 1.3 x 10 ⁴ cells /mL of NCI-H1581 cell suspension, and the resultant was cultured overnight in a 5% CO ₂ incubator (37°C). On the next day, 50 μl of a test substance diluted with RPMI-1640 medium containing 10% FBS was added to each well, and the resultant was cultured in a 5% CO ₂ incubator (37° C.) for 3 days. 10 μL of Cell Counting Kit-8 (Dojindo Laboratories, CK04) was added to each well, and the resultant was cultured in a ₅ % CO incubator (37° C.) for 2 to 3 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd.) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained without the addition of the test substance is 100% and the absorbance obtained in wells containing no cells is 0%, the absorbance ratio in the presence of the test substance is obtained. The concentration of each test substance required to inhibit the cell growth by 50% (ie, IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance is shown in Table 31.

<Evaluation data of growth inhibitory effect of NCI-H1581>

[Table 31]

8. Antitumor effect in a mouse model with subcutaneously implanted SNU-16

Cells of the human gastric cancer cell line SNU-16 (which had been cultured in ¹⁰ % FBS and penicillin/streptomycin in RPMI-1640 medium), and the resultant was mixed with MATRIGEL (BD Biosciences (BD Biosciences Company), Cat# 354234) at a ratio of 1:1 to prepare a ⁵ x 107 Cell suspension at a concentration of cells/ml. A volume of 100 µL of this suspension was implanted into the subcutaneous part of the right flank of each nude mouse (BALB/cAJcl-nu/nu, female, CleaJapan Inc.) at 6 to 7 weeks old. Seven days after implantation, the shortest and longest diameters of the resulting tumor were measured for each mouse by using an electronic digital caliper (DigimaticTM caliper, Mitutoyo Corporation (Japan)) to calculate the tumor according to the following calculation formula volume of:

Tumor volume (mm ³ )=(longest diameter (mm))×(shortest diameter (mm))×(shortest diameter (mm))/2

Based on the volume of tumors obtained on the first day of dosing, the mice were grouped such that the mean tumor volumes in the groups were approximately equal. Each test substance was dissolved in DMSO, Tween 80 was added thereto to prepare a 10-fold concentration solution, and the thus prepared solution was frozen and stored. A 5% glucose solution was added thereto immediately before administration to obtain a final administration solution (wherein the ratio in % of DMSO, Tween 80 and the 5% glucose solution was 3.5:6.5:90). Each evaluation sample was orally administered at a dose of 20 mL/kg once a day for 11 days, and in the control group, the administration vehicle was orally administered under the same conditions. Incidentally, this experiment was carried out in groups each consisting of 5 mice.

The ratio of the body weight measured on the last day to the body weight measured on the first day (relative body weight: RBW) was calculated for each control group and test substance-administered group. If the ratio of RBW of the test substance-administered group/RBW of the control group was 0.9 or higher, the corresponding test substance-administered group was determined as a safe-administrable group. In the test substance administration group thus determined to be safe to administer, the ratio (T/C) (%) of the tumor volume obtained after administration of the test substance obtained on the last day to the tumor volume of the control group was calculated, and Such ratios for the respective test substances thus calculated are shown in Table 32.

<Evaluation data of antitumor effect in a model with subcutaneously implanted SNU-16>

[Table 32]

9. Anti-tumor effect in a mouse model with subcutaneously implanted NCI-H1581

Cells of the human lung cancer cell line NCI- ^H1581 (ATCC number CRL-5878) (their have been cultured in RPMI-1640 medium containing 10% fetal bovine serum, penicillin and streptomycin) to prepare a cell suspension. Furthermore, the resulting suspension was mixed with MATRIGEL at a ratio of 1:1 to prepare a cell suspension having a concentration of 5 x 10 ⁷ cells/mL. A volume of 100 μL of this cell suspension was implanted into the subcutaneous part of the right flank of each nude mouse (BALB/cAJcl-nu/nu, female, Clea Japan Inc.) at 6 to 7 weeks old. Ten to 11 days after the implantation, the shortest and longest diameters of the resulting tumors of each mouse were measured by using an electronic digital caliper (Digimatic TM caliper, Mitutoyo Corporation (Japan)), to be calculated according to the following The formula calculates the volume of the tumor:

Tumor volume (mm ³ )=(longest diameter (mm))×(shortest diameter (mm))×(shortest diameter (mm))/2

Based on the volume of tumors obtained on the first day of administration, the nude mice were grouped so that the average tumor volumes in these groups were approximately equal. Each test substance was dissolved in DMSO, Tween 80 was added thereto to prepare a stock solution of 10-fold concentration of the evaluation sample, and the solution thus prepared was frozen and stored until use. The stock solution was diluted with 5% glucose solution immediately before administration to obtain an evaluation sample (wherein the ratio in % of DMSO, Tween 80 and the 5% glucose solution was 3.5:6.5:90). In a test substance administration group, the evaluation sample was orally administered at a dose of 0.4 mL per 20 g body weight once a day for 11 days, and in a control group, the administration solvent was orally administered under the same conditions. Incidentally, this experiment was carried out in groups each consisting of 5 mice.

The ratio of the body weight measured on the last day to the body weight measured on the first day (relative body weight: RBW) was calculated for each control group and test substance-administered group. If the ratio of RBW of the test substance-administered group/RBW of the control group was 0.9 or higher, the corresponding test substance-administered group was determined as a safe-administered group. In the test substance administration group thus determined to be safe to administer, the ratio (T/C) (%) of the tumor volume obtained after administration of the test substance obtained on the last day to the tumor volume of the control group was calculated, and Such ratios for the respective test substances thus calculated are shown in Table 33.

<Evaluation data of antitumor effect in a model with subcutaneously implanted NCI-H1581>

[Table 33]

10. AN3CA Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance is measured in a human endometrial carcinoma cell line expressing the N549K variant FGFR2.

It has been reported that the human endometrial cancer cell line AN3CA (ATCC code HTB-111) expresses the N549K variant FGFR2 (Proc Natl Acad Sci USA, 2008, 105:8713-8717). By using RPMI-1640 (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.), 168-23191) containing 10% FBS, penicillin and streptomycin Pharmaceutical Industry Co., Ltd., 187-02021) culture medium AN3CA cells were maintained in a 5% CO ₂ incubator (37°C). Add 150 μL of RPMI-1640 medium containing 10% FBS, penicillin and streptomycin to a concentration of 1.3 x 10 ⁴ cells/mL of AN3CA cell suspension, and these cells were cultured overnight in a 5% CO ₂ incubator (37°C). On the next day, 50 μl of a test substance diluted with RPMI-1640 medium containing 10% FBS, penicillin, and streptomycin was added to each well, and the resultant was incubated in a 5% _CO incubator (37° C.) cultured for 3 days. 10 μL of Cell Counting Kit-8 (Dojindo Laboratories, CK04) was added to each well, and the resultant was cultured in a 5% _CO incubator (37° C.) for 1 to 2 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd.) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained in the wells containing the cells but not the test substance is 100% and the absorbance obtained in the wells not containing the cells is 0%, the absorbance ratio in the presence of the test substance is obtained. The concentration of the test substance required to inhibit the cell growth by 50% (ie, the IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance is shown in Table 34.

<Evaluation data of growth inhibitory effect of AN3CA>

[Table 34]

11. MFE296 Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance is measured in a human endometrial carcinoma cell line expressing the N549K variant FGFR2.

It has been reported that the human endometrial cancer cell line MFE296 (DSMZ number ACC-419) expresses the N549K variant FGFR2 (Proc Natl Acad Sci USA, 2008, 105:8713-8717). By using RPMI-1640 (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.), 168-23191) containing 10% FBS, penicillin and streptomycin Pharmaceutical Industry Co., Ltd.), 187-02021) culture medium MFE296 cells were maintained in a 5% CO ₂ incubator (37°C). Add 150 μL of RPMI-1640 medium containing 10% FBS, penicillin and streptomycin to a concentration of 1.3 x 10 ⁴ cells/mL of MFE296 cell suspension, and these cells were cultured overnight in a 5% CO ₂ incubator (37°C). On the next day, 50 μl of a test substance diluted with RPMI-1640 medium containing 10% FBS, penicillin, and streptomycin was added to each well, and the resultant was incubated in a 5% _CO incubator (37° C.) cultured for 3 days. 10 μL of Cell Counting Kit-8 (Dojindo Laboratories, CK04) was added to each well, and the resultant was cultured in a 5% _CO incubator (37° C.) for 1 to 2 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd.) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained in the wells containing the cells but not the test substance is 100% and the absorbance obtained in the wells not containing the cells is 0%, the absorbance ratio in the presence of the test substance is obtained. The concentration of the test substance required to inhibit the cell growth by 50% (ie, the IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance is shown in Table 35.

<Evaluation data of growth inhibitory effect of MFE296>

[Table 35]

12. MFE280 Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance was measured in a human endometrial carcinoma cell line expressing the S252W variant FGFR2.

It has been reported that the human endometrial cancer cell line MFE280 (DMSZ number ACC-410) expresses the S252W variant FGFR2 (Proc Natl Acad Sci USA, 2008, 105:8713-8717). By using RPMI-1640 (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.), 168-23191) containing 10% FBS, penicillin and streptomycin Pharmaceutical Industry Co., Ltd., 187-02021) culture medium MFE280 cells were maintained in a 5% CO ₂ incubator (37°C). Add 150 μL of RPMI-1640 medium containing 10% FBS, penicillin and streptomycin to a concentration of 3.3×10 ⁴ cells/mL of MFE280 cell suspension, and these cells were cultured overnight in a 5% CO ₂ incubator (37° C.). On the next day, 50 μl of a test substance diluted with RPMI-1640 medium containing 10% FBS, penicillin, and streptomycin was added to each well, and the resultant was incubated in a 5% _CO incubator (37° C.) cultured for 3 days. 10 μL of Cell Counting Kit-8 (Dojindo Laboratories, CK04) was added to each well, and the resultant was cultured in a 5% _CO incubator (37° C.) for 1 to 2 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd.) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained in the wells containing the cells but not the test substance is 100% and the absorbance obtained in the wells not containing the cells is 0%, the absorbance ratio in the presence of the test substance is obtained. The concentration of the test substance required to inhibit the cell growth by 50% (ie, the IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance is shown in Table 36.

<Evaluation data of growth inhibitory effect of MFE280>

[Table 36]

13. Anti-tumor effect in a mouse model with subcutaneously implanted AN3CA

Cells of the human endometrial cancer cell line AN3CA (ATCC number HTB-111) were purified by using Hanks' Balanced Salt Solution (GIBCO #24020) at a concentration of ¹ x 108 cells/mL ( It has been cultured in RPMI-1640 medium containing 10% fetal bovine serum, penicillin and streptomycin) prepared as a cell suspension. The resulting cell suspension was mixed with MATRIGEL (BD Biosciences, Cat#354234) at a ratio of 1:1 to prepare a cell suspension with a concentration of 5 x 10 ⁷ cells/ml. A volume of 100 µL of this cell suspension was implanted into the subcutaneous portion of the right flank of each nude mouse (BALB/cAJcl-nu/nu, female, Clea Japan Inc.) at 7 weeks old. Eleven days after the implantation, the shortest and longest diameters of the resulting tumors of each mouse were measured by using electronic digital calipers (Digimatic TM calipers, Mitutoyo Corporation (Japan Mitutoyo Corporation)) to calculate according to the following formula Calculate the volume of this tumor:

Tumor volume (mm ³ )=(longest diameter (mm))×(shortest diameter (mm))×(shortest diameter (mm))/2

Based on the volume of tumors obtained on the first day of administration, the nude mice were grouped so that the average tumor volumes in these groups were approximately equal. Each test substance was dissolved in DMSO, Tween 80 was added thereto to prepare a stock solution of 10-fold concentration of the evaluation sample, and the solution thus prepared was frozen and stored until use. The stock solution was diluted with 5% glucose solution immediately before administration to obtain an evaluation sample (wherein the ratio in % of DMSO, Tween 80 and the 5% glucose solution was 3.5:6.5:90). In a test substance administration group, the evaluation sample was orally administered at a dose of 0.4 mL per 20 g body weight once a day for 14 days, and in the control group, the administration solvent was orally administered under the same conditions. Incidentally, this experiment was carried out in groups each consisting of 5 mice.

The ratio of the body weight measured on the last day to the body weight measured on the first day (relative body weight: RBW) was calculated for each control group and test substance-administered group. If the ratio of RBW of the test substance-administered group/RBW of the control group was 0.9 or higher, the corresponding test substance-administered group was determined as a safe-administered group. In the test substance administration group thus determined to be safe to administer, the ratio (T/C) (%) of the tumor volume obtained after administration of the test substance obtained on the last day to the tumor volume of the control group was calculated, and Such ratios for the respective test substances thus calculated are shown in Table 37.

<Evaluation data of antitumor effect in mouse model with subcutaneous implantation of AN3CA>

[Table 37]

14. Anti-tumor effect in a mouse model with subcutaneously implanted MFE296

Cells of the human endometrial cancer cell line MFE296 (DSMZ number ACC-419) were purified by using Hanks' Balanced Salt Solution (GIBCO #24020) at a concentration of ¹ x 108 cells/mL ( It has been cultured in RPMI-1640 medium containing 10% fetal bovine serum, penicillin and streptomycin) prepared as a cell suspension. The resulting cell suspension was mixed with MATRIGEL (BD Biosciences, Cat#354234) at a ratio of 1:1 to prepare a cell suspension with a concentration of 5 x 10 ⁷ cells/ml. A volume of 100 µL of this cell suspension was implanted into the subcutaneous portion of the right flank of each nude mouse (BALB/cAJcl-nu/nu, female, Clea Japan Inc.) at 7 weeks old. Twelve days after the implantation, the shortest and longest diameters of the resulting tumors of each mouse were measured by using an electronic digital caliper (DigimaticTM caliper, Mitutoyo Corporation (Japan Mitutoyo Corporation)), to be calculated according to the following calculation formula The volume of the tumor:

Tumor volume (mm ³ )=(longest diameter (mm))×(shortest diameter (mm))×(shortest diameter (mm))/2

Based on the volume of tumors obtained on the first day of administration, the nude mice were grouped so that the average tumor volumes in these groups were approximately equal. Each test substance was dissolved in DMSO, Tween 80 was added thereto to prepare a stock solution of 10-fold concentration of the evaluation sample, and the solution thus prepared was frozen and stored until use. The stock solution was diluted with 5% glucose solution immediately before administration to obtain an evaluation sample (wherein the ratio in % of DMSO, Tween 80 and the 5% glucose solution was 3.5:6.5:90). In a test substance administration group, the evaluation sample was orally administered at a dose of 0.4 mL per 20 g of body weight once a day for 14 days, and in a control group, the administration solvent was orally administered under the same conditions. Incidentally, this experiment was carried out in groups each consisting of 5 mice.

The ratio of the body weight measured on the last day to the body weight measured on the first day (relative body weight: RBW) was calculated for each control group and test substance-administered group. If the ratio of RBW of the test substance-administered group/RBW of the control group was 0.9 or higher, the corresponding test substance-administered group was determined as a safe-administered group. In the test substance administration group thus determined to be safe to administer, the ratio (T/C) (%) of the tumor volume obtained after administration of the test substance obtained on the last day to the tumor volume of the control group was calculated, and Such ratios for the respective test substances thus calculated are shown in Table 38.

<Evaluation data of antitumor effect in mouse model with subcutaneous implantation of MFE296>

[Table 38]

15. Anti-tumor effect in a mouse model with subcutaneously implanted MFE280

Cells of the human endometrial cancer cell line MFE280 (DMSZ number ACC-410) were purified by using Hanks' Balanced Salt Solution (GIBCO# ²⁴⁰²⁰ ) at a concentration of 4.7 x 107 cells/mL ( It has been cultured in RPMI-1640 medium containing 10% fetal bovine serum, penicillin and streptomycin) prepared as a cell suspension. The resulting cell suspension was mixed with MATRIGEL (BD Biosciences, Cat#354234) at a ratio of 1:1 to prepare a cell suspension with a concentration of 2.4 x 10 ⁷ cells/ml. A volume of 100 µL of this cell suspension was implanted into the subcutaneous portion of the right flank of each nude mouse (BALB/cAJcl-nu/nu, female, Clea Japan Inc.) at 7 weeks old. Thirty-five days after implantation, the shortest and longest diameters of the resulting tumors in each mouse were measured by using an electronic digital caliper (DigimaticTM caliper, Mitutoyo Corporation (Japan Mitutoyo Corporation)) to calculate according to the following formula Calculate the volume of this tumor:

Tumor volume (mm ³ )=(longest diameter (mm))×(shortest diameter (mm))×(shortest diameter (mm))/2

Based on the volume of tumors obtained on the first day of administration, the nude mice were grouped so that the average tumor volumes in these groups were approximately equal. Each test substance was dissolved in DMSO, Tween 80 was added thereto to prepare a stock solution of 10-fold concentration of the evaluation sample, and the solution thus prepared was frozen and stored until use. The stock solution was diluted with 5% glucose solution immediately before administration to obtain an evaluation sample (wherein the ratio in % of DMSO, Tween 80 and the 5% glucose solution was 3.5:6.5:90). In a test substance administration group, the evaluation sample was orally administered at a dose of 0.4 mL per 20 g of body weight once a day for 14 days, and in a control group, the administration solvent was orally administered under the same conditions. Incidentally, this experiment was carried out in groups each consisting of 5 mice.

The ratio of the body weight measured on the last day to the body weight measured on the first day (relative body weight: RBW) was calculated for each control group and test substance-administered group. If the ratio of RBW of the test substance-administered group/RBW of the control group was 0.9 or higher, the corresponding test substance-administered group was determined as a safe-administered group. In the test substance administration group thus determined to be safe to administer, the ratio (T/C) (%) of the tumor volume obtained after administration of the test substance obtained on the last day to the tumor volume of the control group was calculated, and Such ratios for the respective test substances thus calculated are shown in Table 39.

<Evaluation data of antitumor effect in mouse model with subcutaneous implantation of MFE280>

[Table 39]

16. RT112/84 Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance was measured in a human bladder cancer cell line expressing a FGFR3-TACC3 fusion protein.

By using RPMI-1640 (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.), 168-23191) containing 10% FBS, penicillin and streptomycin (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd., Japan) Kogyo Co., Ltd., 187-02021) culture medium The cells of the human bladder cancer cell line RT112/84 (ECACC No. EC85061106-F0) were maintained and cultured in a 5% CO ₂ incubator (37°C). Add 150 μL of RPMI-1640 medium containing 10% FBS, penicillin and streptomycin to a concentration of 1.3 x 10 ⁴ cells/mL of RT112/84 cell suspension, and these cells were cultured overnight in a 5% CO ₂ incubator (37°C). On the next day, 50 μL of a test substance solution diluted with RPMI-1640 medium containing 10% FBS and penicillin and streptomycin was added to each well, and the resultant was incubated in a 5% _CO incubator (37° C. ) for 3 days. After that, 10 μL of Cell Counting Kit (Cell Counting Kit)-8 (Dojindo Laboratories (Dojindo Institute of Chemistry), CK04) was added to each well, and the resultant was incubated in a 5% _CO incubator (37° C. ) for 1 to 2 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd.) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained in the wells of a cell suspension containing the cells but not the test substance is 100% and the absorbance obtained in the wells not containing the cells is 0%, obtain the absorbance in the presence of the test substance ratio. The concentration of the test substance required to inhibit the cell growth by 50% (ie, the IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance is shown in Table 40.

<Evaluation data of growth inhibitory effect of RT112/84>

[Table 40]

17. SW780 Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance was measured in a human bladder cancer cell line expressing the FGFR3-BAIAP2L1 fusion protein.

It has been reported that human bladder cancer cell line SW780 (ATCC accession number CRL-2169) expresses FGFR3-BAIAP2L1 fusion protein (Hum Mol Genet. ("Human Molecular Genetics") 2013, 22: 795-803). By using RPMI-1640 (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.), 168-23191) containing 10% FBS, penicillin and streptomycin Pharmaceutical Industry Co., Ltd., 187-02021) culture medium to maintain SW780 cells in a 5% CO ₂ incubator (37°C). Add 150 μL of RPMI-1640 medium containing 1% FBS, penicillin and streptomycin to a concentration of 2.6 x 10 ⁴ cells/mL of SW780 cell suspension, and these cells were cultured overnight in a 5% CO ₂ incubator (37°C). On the next day, 50 μL of a test substance diluted with RPMI-1640 medium containing 1% FBS, penicillin, and streptomycin was added to each well, and the resultant was incubated in a 5% CO ₂ incubator (37° C.) cultured for 3 days. 10 μL of CellCounting Kit-8 (Dojindo Laboratories, CK04) was added to each well, and the resultant was incubated in a 5% _CO incubator (37° C.) for 1 to 2 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd. (PerkinElmer Co., Ltd.)) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained in the wells containing the cells but not the test substance is 100% and the absorbance obtained in the wells not containing the cells is 0%, the absorbance ratio in the presence of the test substance is obtained. The concentration of the test substance required to inhibit the cell growth by 50% (ie, the IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance is shown in Table 41.

<Evaluation data of growth inhibitory effect of SW780>

[Table 41]

18. RT4 Growth Inhibition Assay

In this assay, the growth inhibitory activity of a test substance was measured in a human bladder cancer cell line expressing a FGFR3-TACC3 fusion protein.

It has been reported that the human bladder cancer cell line RT4 (ATCC code HTB-2) expresses FGFR3-TACC3 fusion protein (Hum Mol Genet. ("Human Molecular Genetics") 2013, 22:795-803). By using RPMI-1640 (Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.), 168-23191) containing 10% FBS, penicillin and streptomycin Pharmaceutical Industry Co., Ltd., 187-02021) medium, RT4 cells were maintained in a 5% CO ₂ incubator (37°C). Add 150 μL of RPMI-1640 medium containing 10% FBS, penicillin and streptomycin to a concentration of 2.6 x 10 ⁴ cells/mL of RT4 cell suspension, and these cells were cultured overnight in a 5% CO ₂ incubator (37°C). On the next day, 50 μl of a test substance diluted with RPMI-1640 medium containing 10% FBS, penicillin, and streptomycin was added to each well, and the resultant was incubated in a 5% _CO incubator (37° C.) cultured for 3 days. 10 μL of Cell Counting Kit (Cell Counting Kit)-8 (Dojindo Laboratories (Dojindo Chemical Research Institute), CK04) was added to each well, and the resultant was incubated in a 5% CO ₂ incubator (37° C.) for 1 to 2 hours to induce a color reaction. ENVISION(TM) (PerkinElmer Co., Ltd.) was used for measuring absorbance at 450 nm. Assuming that the absorbance obtained in the wells containing the cells but not the test substance is 100% and the absorbance obtained in the wells not containing the cells is 0%, the absorbance ratio in the presence of the test substance is obtained. The concentration of the test substance required to inhibit the cell growth by 50% (ie, the IC ₅₀ value) was calculated, and the thus calculated IC ₅₀ value of each test substance is shown in Table 42.

<Evaluation data of growth inhibitory effect of RT4>

[Table 42]

19. Anti-tumor effect in a mouse model with subcutaneously implanted RT112/84

Cells of the human cancer cell line RT112/84 (ECACC number ^EC85061106 -F0) (which had been cultured in RPMI-1640 medium containing 10% fetal bovine serum, penicillin and streptomycin) prepared as a cell suspension. The resulting suspension was mixed with MATRIGEL (BD Biosciences, Cat#354234) at a ratio of 1:1 to prepare a cell suspension with a concentration of 5×10 ⁷ cells/ml. A volume of 100 µL of this cell suspension was implanted into the subcutaneous portion of the right flank of each nude mouse (BALB/cAJcl-nu/nu, female, Clea Japan Inc.) at 7 weeks old. Ten days after the implantation, the shortest and longest diameters of the resulting tumors of each mouse were measured by using an electronic digital caliper (Digimatic TM caliper, Mitutoyo Corporation (Japan Mitutoyo Corporation)), to be calculated according to the following calculation formula The volume of the tumor:

Tumor volume (mm ³ )=(longest diameter (mm))×(shortest diameter (mm))×(shortest diameter (mm))/2

Based on the volume of tumors obtained on the first day of administration, the nude mice were grouped so that the average tumor volumes in these groups were approximately equal. Each test substance was dissolved in DMSO, Tween 80 was added thereto to prepare a stock solution of 10-fold concentration of the evaluation sample, and the solution thus prepared was frozen and stored until use. The stock solution was diluted with 5% glucose solution immediately before administration to obtain an evaluation sample (wherein the ratio in % of DMSO, Tween 80 and the 5% glucose solution was 3.5:6.5:90). In a test substance administration group, the evaluation sample was orally administered at a dose of 0.4 mL per 20 g of body weight once a day for 14 days, and in a control group, the administration solvent was orally administered under the same conditions. Incidentally, this experiment was carried out in groups each consisting of 5 mice.

The ratio of the body weight measured on the last day to the body weight measured on the first day (relative body weight: RBW) was calculated for each control group and test substance-administered group. If the ratio of RBW of the test substance-administered group/RBW of the control group was 0.9 or higher, the corresponding test substance-administered group was determined as a safe-administered group. In the test substance administration group thus determined to be safe to administer, the ratio (T/C) (%) of the tumor volume obtained after administration of the test substance obtained on the last day to the tumor volume of the control group was calculated, and Such ratios for the respective test substances thus calculated are shown in Table 43.

<Evaluation data of antitumor effect in mouse model with subcutaneous implantation of RT112/84>

[Table 43]

Claims (22)

1. A compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof: in n stands for 0 to 2; A represents C _6-10 arylene; G represents a single bond, an oxygen atom or -CH ₂ -; E represents a C _3-5 nitrogen-containing non-aromatic heterocycle; R ¹ represents cyano, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _2-6 alkyl optionally substituted by 1 to 3 halogen atoms, optionally substituted by 1 C 1-6 alkoxy substituted by 1 to 3 halogen atoms or one hydroxy group, C _1-6 alkoxy C _{1-6 alkyl} optionally substituted by 1 to 3 halogen atoms, or optionally substituted by 1 C _1-6 alkoxy C _1-6 alkoxy substituted by 3 halogen atoms; R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _2-6 acyl group optionally substituted by a substituent selected from the group S described below, a C ₁ optionally substituted by 1 to 3 halogen atoms _-6 alkyl, hydroxy C _1-6 alkyl optionally substituted by 1 to 3 halogen atoms, or C _3-5 nitrogen-containing non-aromatic heterocyclic group; R ³ represents a hydrogen atom, an oxo group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C _1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms; R ⁴ represents a C _1-6 alkyl group, with the proviso that when E represents an azetidine ring and R ² or R ³ exists on a nitrogen atom on the azetidine ring, the R ² or R ³ does not represent a hydrogen atom; and The group S represents a group consisting of: hydroxyl, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkoxy and C _{3 -5} nitrogen-containing non-aromatic heterocyclic group. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, represented by the following formula (IB): in n stands for 0 to 2; A represents C _6-10 arylene; G represents a single bond, an oxygen atom or -CH ₂ -; E represents a C _3-5 nitrogen-containing non-aromatic heterocycle; R ¹ represents C _1-6 alkoxy optionally substituted by 1 to 3 halogen atoms or a hydroxyl group, or C _1-6 alkoxy C _1-6 optionally substituted by 1 to 3 halogen atoms alkoxy; R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, a hydroxy C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C _3-5 nitrogen-containing non-aromatic heterocyclic group; and R ³ represents a hydrogen atom, an oxo group, a C _1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C _1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, The proviso is that when E represents an azetidine ring and R2 or ^R3 is present ^on a nitrogen atom on the azetidine ring, this R2 or ^R3 does not represent a ^hydrogen atom. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G represents a single bond or an oxygen atom. 4. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein A represents phenylene; and E represents an azetidine ring, a pyrrolidine ring, a piperidine ring or a piperazine ring. 5. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein A represents phenylene; and E represents an azetidine ring or a piperidine ring. 6. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein A represents phenylene; and E represents a piperidine ring. 7. The compound or pharmaceutically acceptable salt thereof according to claim 4, wherein n represents 0; and G stands for single bond. 8. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R represents C ^1-6 alkoxy or C _1-6 alkoxy C _{1-6 alkoxy} ; R ² represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group or a hydroxy C _1-6 alkyl group; and R ³ represents a hydrogen atom. 9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ represents C _1-6 alkoxy C _1-6 alkoxy. 10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the following formula (II): in R ¹ represents C _1-6 alkoxy C _1-6 alkoxy; and R ² represents a hydrogen atom, a C _1-6 alkyl group or a hydroxy C _2-6 alkyl group. 11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by the following formula (III): in R ¹ represents C _1-6 alkoxy C _1-6 alkoxy; and R ² represents C _1-6 alkyl or hydroxy C _2-6 alkyl. 12. 5-(((2-(4-(1-ethylpiperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6-methoxy-N represented by the following structural formula -Methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof: 13. 6-(2-methoxyethoxy)-N-methyl-5-((2-(4-(1-methylpiperidin-4-yl))benzamide represented by the following structural formula )pyridin-4-yl)oxy)-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof: 14. 5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide)pyridin-4-yl)oxy)-6- represented by the following structural formula (2-Methoxyethoxy)-N-methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof: 15. 6-(2-ethoxyethoxy)-5-((2-(4-(1-(2-hydroxyethyl)piperidin-4-yl)benzamide represented by the following structural formula )pyridin-4-yl)oxy)-N-methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof: 16. 6-(2-ethoxyethoxy)-5-((2-(4-(1-ethylazetidin-3-yl)benzamide)pyridine represented by the following structural formula -4-yl)oxy)-N-methyl-1H-indole-1-carboxamide, or a pharmaceutically acceptable salt thereof: 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof. 18. A therapeutic agent for gastric cancer, non-small cell lung cancer, bladder cancer or endometrial cancer, comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient. 19. A therapeutic agent for non-small cell lung cancer comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient. 20. A therapeutic agent for squamous cell carcinoma comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient. 21. An FGFR inhibitor for treating non-small cell lung cancer, comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient. 22. Use of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic agent for gastric cancer, non-small cell lung cancer, bladder cancer or endometrial cancer.